Pyrazolopyrimidines and related analogs as HSP90-inhibitors

ABSTRACT

Pyrazolopyrimidines and related analogs are described and demonstrated or predicted to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Method of synthesis and use of such compounds are also described and claimed.

This application relates and claims priority to U.S. ProvisionalApplication Ser. No. 60/504,135, filed Sep. 18, 2003, entitled NOVELHETEROCYCLIC COMPOUNDS AS HSP90 INHIBITORS and U.S. ProvisionalApplication Ser. No. 60/591,467, filed Jul. 26, 2004, entitled2-AMINOPURINE ANALOGS HAVING HSP90-INHIBITING ACTIVITY. This applicationalso relates to three other United States Utility Applications, entitled2-AMINOPURINE ANALOGS AS HSP90 INHIBITOR, PYRROLOPYRIMIDINES AND RELATEDANALOGS AS HSP90 INHIBITORS, and TRIAZOPYRIMIDES AND RELATED ANALOGS ASHSP90 INHIBITORS, which will be filed on the same date by the sameentity. This application further relates to International ApplicationPCT/US02/35069, filed Oct. 30, 2002, entitled PURINE ANALOGS HAVINGHSP90-INHIBITING ACTIVITY. All the above cited U.S. utilityapplications, provisional applications and international application areexpressly incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates in general to pyrazolopyrimidines and theirrelated analogs and their broad-spectrum utility, e.g., in inhibitingheat shock protein 90 (HSP90) to thereby treat or prevent HSP90-mediateddiseases.

BACKGROUND

HSP90s are ubiquitous chaperone proteins that are involved in folding,activation and assembly of a wide range of proteins, including keyproteins involved in signal transduction, cell cycle control andtranscriptional regulation. Researchers have reported that HSP90chaperone proteins are associated with important signaling proteins,such as steroid hormone receptors and protein kinases, including, e.g.,Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner J. TIBS1999, 24, 136-141; Stepanova, L. et al. Genes Dev. 1996, 10, 1491-502;Dai, K. et al. J. Biol. Chem. 1996, 271, 22030-4). Studies furtherindicate that certain co-chaperones, e.g., HSP70, p60/Hop/Sti1, Hip,Bag1, HSP40/Hdj2/Hsj1, immunophilins, p23, and p50, may assist HSP90 inits function (see, e.g., Caplan, A. Trends in Cell Biol. 1999, 9,262-68).

Ansamycin antibiotics, e.g, herbimycin A (HA), geldanamycin (GM), and17-allylaminogeldanamycin (17-AAG) are thought to exert theiranticancerous effects by tight binding of the N-terminus pocket ofHSP90, thereby destabilizing substrates that normally interact withHSP90 (Stebbins, C. et al. Cell 1997, 89, 239-250). This pocket ishighly conserved and has weak homology to the ATP-binding site of DNAgyrase (Stebbins, C. et al., supra; Grenert, J. P. et al. J. Biol. Chem.1997, 272, 23843-50). Further, ATP and ADP have both been shown to bindthis pocket with low affinity and to have weak ATPase activity(Proromou, C. et al. Cell 1997, 90, 65-75; Panaretou, B. et al. EMBO J.1998, 17, 4829-36). In vitro and in vivo studies have demonstrated thatoccupancy of this N-terminal pocket by ansamycins and other HSP90inhibitors alters HSP90 function and inhibits protein folding. At highconcentrations, ansamycins and other HSP90 inhibitors have been shown toprevent binding of protein substrates to HSP90 (Scheibel, T. H. et al.Proc. Natl. Acad. Sci. USA 1999, 96, 1297-302; Schulte, T. W. et al. J.Biol. Chem. 1995, 270, 24585-8; Whitesell, L., et al. Proc. Natl. Acad.Sci. USA 1994, 91, 8324-8328). Ansamycins have also been demonstrated toinhibit the ATP-dependent release of chaperone-associated proteinsubstrates (Schneider, C. L. et al. Proc. Natl. Acad. Sci., USA 1996,93, 14536-41; Sepp-Lorenzino et al. J. Biol. Chem. 1995, 270,16580-16587). In either event, the substrates are degraded by aubiquitin-dependent process in the proteasome (Schneider, C. L., supra;Sepp-Lorenzino, L., et al. J. Biol. Chem. 1995, 270, 16580-16587;Whitesell, L. et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328).

HSP90 substrate destabilization occurs in tumor and non-transformedcells alike and has been shown to be especially effective on a subset ofsignaling regulators, e.g., Raf (Schulte, T. W. et al. Biochem. Biophys.Res. Commun. 1997, 239, 655-9; Schulte, T. W., et al. J. Biol. Chem.1995, 270, 24585-8), nuclear steroid receptors (Segnitz, B.; U. GehringJ. Biol. Chem. 1997, 272, 18694-18701; Smith, D. F. et al. Mol. Cell.Biol. 1995, 15, 6804-12), v-Src (Whitesell, L., et al. Proc. Natl. AcadSci. USA 1994, 91, 8324-8328) and certain transmembrane tyrosine kinases(Sepp-Lorenzino, L. et al. J. Biol. Chem. 1995, 270, 16580-16587) suchas EGF receptor (EGFR) and HER2/Neu (Hartmann, F., et al. Int. J. Cancer1997, 70, 221-9; Miller, P. et al. Cancer Res. 1994, 54, 2724-2730;Mimnaugh, E. G., et al. J. Biol. Chem. 1996, 271, 22796-801; Schnur, R.et al. J. Med Chem. 1995, 38, 3806-3812), CDK4, and mutant p53.Erlichman et al. Proc. AACR 2001, 42, abstract 4474. Theansamycin-induced loss of these proteins leads to the selectivedisruption of certain regulatory pathways and results in growth arrestat specific phases of the cell cycle (Muise-Heimericks, R. C. et al. J.Biol. Chem. 1998, 273, 29864-72), and apoptosis, and/or differentiationof cells so treated (Vasilevskaya, A. et al. Cancer Res., 1999, 59,3935-40). Ansamycins thus hold great promise for the treatment and/orprevention of many types of cancers and proliferative disorders, andalso hold promise as traditional antibiotics. However, their relativeinsolubility makes them difficult to formulate and administer, and theyare not easily synthesized and currently must, at least in part, begenerated through fermentation. Further, the dose limiting toxicity ofansamycins is hepatic.

In addition to anti-cancer and antitumorgenic activity, HSP90 inhibitorshave also been implicated in a wide variety of other utilities,including use as anti-inflammation agents, anti-infectious diseaseagents, agents for treating autoimmunity, agents for treating stroke,ischemia, multiple sclerosis, cardiac disorders, central nervous systemrelated disorders and agents useful in promoting nerve regeneration(See, e.g., Rosen et al. WO 02/09696 (PCT/USO1/23640); Degranco et al.WO 99/51223 (PCT/US99/07242); Gold, U.S. Pat. No. 6,210,974 BI; DeFrancoet al., U.S. Pat. No. 6,174,875. Overlapping somewhat with the above,there are reports in the literature that fibrogenetic disordersincluding but not limited to scleroderma, polymyositis, systemic lupus,rheumatoid arthritis, liver cirrhosis, keloid formation, interstitialnephritis, and pulmonary fibrosis also may be treatable with HSP90inhibitors. Strehlow, WO 02/02123 (PCT/US01/20578). Still further HSP90modulation, modulators and uses thereof are reported in Application Nos.PCT/US03/04283, PCT/US02/35938, PCT/US02/16287, PCT/US02/06518,PCT/US98/09805, PCT/US00/09512, PCT/US01/09512, PCT/US01/23640,PCT/US01/46303, PCT/US01/46304, PCT/US02/06518, PCT/US02/29715,PCT/US02/35069, PCT/US02/35938, PCT/US02/39993, 60/293,246, 60/371,668,60/335,391, 60/128,593, 60/337,919, 60/340,762, 60/359,484 and60/331,893.

Recently, purine derivatives showing HSP90 inhibitory activity have beenreported, e.g., in PCT/US02/35069 and PCT/US02/36075. Purine moietiesare well accepted bioisosteres for a variety of ATP-dependent moleculartargets, see, JP 10025294; US Patent 4,748,177; U.S. Pat. No. 4,772,606;U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO02/055083; EP 0178178; Eur. J. Med. Chem. 1994, 29(1), 3-9; and J. Het.Chem. 1990, 27(5), 1409. However, compounds having the desired potency,selectivity and pharmaceutical properties required for effective HSP90inhibition in vivo have not been reported. Therefore, a need remains foradditional novel and potent HSP90 inhibitors that meet the demandingbiological and pharmaceutical criteria required to proceed towards humanclinical trials.

SUMMARY OF THE INVENTION

The present invention is directed towards heterocyclic compounds, inparticular towards pyrazolopyrimidines and related compounds that showbroad utility, e.g., in inhibiting HSP90 and/or treating and preventingdiseases that are HSP90-dependent.

In one aspect, the invention comprises the heterocyclic compounds asspecified below in Formulae A, I and II and compounds that are producedby a synthesis process of the invention. Also included in the scope ofthe present invention are stereoisomeric forms, including the individualenantiomers and diastereomers, racemic mixtures, and diastereomericmixtures, as well as polymorphs, solvates, esters, tautomers,pharmaceutically acceptable salts and prodrugs of these compounds.

In one embodiment, the invention provides compounds of Formula A, or apolymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, which show utilityby inhibiting HSP90 and treating and/or preventing diseases that areHSP90-dependent.

wherein:

-   -   X¹ and X² are the same or different and each is nitrogen or        —CR⁶;    -   X³ is nitrogen or —CR³ wherein R³ is hydrogen, OH, a keto        tautomer, —OR⁸, —CN, halogen, lower alkyl, or -C(O)R⁹;    -   X⁴ is nitrogen or —CR⁶ when X³ is nitrogen; and X⁴ is —CR⁶R⁷        when X³ is —CR³;    -   R¹ is halogen, —OR⁸, —SR⁸, or lower alkyl;    -   R² is —NR⁸R¹⁰;    -   R⁴ is —(CH₂)_(n)— wherein n=0-3, —C(O), —C(S), —SO₂—, or —SO₂N—;        and    -   R⁵ is alkyl, aromatic, heteroaromatic, alicyclic, or        heterocyclic, each of which is optionally bi-or tri-cyclic, and        optionally substituted with H, halogen, lower alkyl, lower        alkenyl, lower alkynyl, lower aryl, lower alicyclic, aralkyl,        aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy,        perhaloacyl, —N₃, —SOR⁸, —CO₂R⁹, —N₂, or —NR⁸R¹⁰.

In certain embodiments, there are exclusionary provisos with respect tocompounds disclosed in JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat.No. 4,748,177; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO02/055082; WO 02/055083; Eur. J. Med Chem. 1994, 29(1), 3-9; and J. Het.Chem. 1990, 27(5), 1409, which disclose compounds with —R⁴R⁵ comprisingribose or a derivative thereof, or a sugar or derivative thereof; andcompounds where —R⁴R⁵is a phosphonate or phosphonic acid, or issubstituted with a phosphonate or phosphonic acid; or compounds where R⁴is —CH₂— or —(CH₂)_(n)— that are connected through an oxygen atom toanother group.

In another embodiment, the invention provides compounds of Formula I, ora polymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, which show utilityfor inhibiting HSP90 and treating and preventing diseases that areHSP90-dependent,

wherein:

-   -   R¹ is halogen, —OR¹¹ —SR¹¹ or lower alkyl;    -   R² is —NHR⁸;    -   R³ is selected from the group consisting of hydrogen, halogen,        —SR⁸, —OR⁸, —CN, —C(O)R⁹, —CO₂H, —NO₂, —NR⁸R¹⁰, lower alkyl,        lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl,        heteroaryl, alicyclic and heterocyclic, all optionally        substituted,        -   wherein:        -   the aryl, heteroaryl, alicyclic and heterocyclic groups are            optionally mono-, bi- or tri-cyclic;        -   R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ring            atoms and optionally 1-2 of the ring atoms are heteroatoms            selected from the group of O, S and N, and        -   the optional substituents on R³ are selected from the group            consisting of halogen, lower alkyl, lower alkenyl, lower            alkynyl, —SR⁸, —OR⁸, —CN, —C(O)R⁹, —C(O)OH, —NO₂, —NR⁸R¹⁰            lower aryl, lower heteroaryl, lower alicyclic, lower            heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,            dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,            perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,            furanyl, indole, indazole, phosphonates, phosphates,            phosphoramides, sulfonates, sulfones, sulfates,            sulphonamides, carbamates, ureas, thioureas and thioamides,            wherein R⁸ and R¹⁰ taken together optionally form a ring of            3-7 ring atoms and optionally 1-3 of the ring atoms are            heteroatoms selected from the group of O, S and N;    -   R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;    -   R⁵is aryl, heteroaryl, alicyclic, or heterocyclic, wherein        -   the aryl group is substituted with 3 to 5 substituents,        -   the heteroaryl group is substituted with 2 to 5            substituents,        -   the alicyclic group is substituted with 3 to 5 substituents,        -   the heterocyclic group is substituted with 3 to 5            substituents, and        -   the substituents on R ⁵are selected from the group            consisting of halogen, lower alkyl, lower alkenyl, lower            alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰            lower aryl, heteroaryl, alicyclic, lower heterocyclic,            arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino,            diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy,            perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,            indole, indazole, phosphonates, phosphates, phosphoramides,            sulfonates, sulfones, sulfates, sulphonamides, carbamates,            ureas, thioureas and thioamides, wherein R⁸ and R¹⁰ taken            together optionally form a ring of 3-7 ring atoms and            optionally 1-3 of the ring atoms are heteroatoms selected            from the group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl or —C(O)R⁹;    -   R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, —NR¹⁰OR¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰        taken together optionally form a ring of 3-7 ring atoms and        optionally 1-3 of the ring atoms are heteroatoms selected from        the group of O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,        lower aryl or lower heteroaryl;    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or        lower heteroaryl; and    -   R¹² is hydrogen or lower alkyl.

In another embodiment, the invention provides compounds of Formula II,or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, which show utilityfor inhibiting HSP90 and treating and/or preventing diseases that areHSP90-dependent,

wherein:

-   -   R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;    -   R² is —NHR⁸;    -   R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;    -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein        -   the aryl group is substituted with 3 to 5 substituents,        -   the heteroaryl group is substituted with 2 to 5            substituents,        -   the alicyclic group is substituted with 3 to 5 substituents,        -   the heterocyclic group is substituted with 3 to 5            substituents, and        -   the substituents on R⁵ are selected from the group            consisting of halogen, lower alkyl, lower alkenyl, lower            alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰            lower aryl, heteroaryl, alicyclic, lower heterocyclic,            arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino,            diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy,            perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,            indole, indazole, phosphonates, phosphates, phosphoramides,            sulfonates, sulfones, sulfates, sulphonamides, carbamates,            ureas, thioureas and thioamides, wherein R⁸ and R¹⁰ taken            together optionally form a ring of 3-7 ring atoms and            optionally 1-3 of the ring atoms are heteroatoms selected            from the group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl or —C(O)R⁹;    -   R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, —NR¹⁰OR¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰        taken together optionally form a ring of 3-7 ring atoms and        optionally 1-3 of the ring atoms are heteroatoms selected from        the group of O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,        lower aryl or lower heteroaryl;    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or        lower heteroaryl; and    -   R¹² is hydrogen or lower alkyl; and    -   R¹⁵ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

In another embodiment, the invention provides compounds, or a polymorph,solvate, ester, tautomer, diastereomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, which show utility for inhibitingHSP90 and treating and/or preventing diseases that are HSP90-dependent,that are prepared by the process comprising:

-   -   reacting a compound of Formula Y and a compound of Formula Z,        wherein:    -   Y is represented by any of the following formulae:    -   Z is L¹-R⁴-R⁵; wherein:        -   L₁ is halogen, NR⁸R¹⁰ triflate, tosylate, or mesylate;        -   R⁴ is —(CHR¹²)—, —C(O), —C(S), —S(O)—, or —SO₂—;        -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein            -   the aryl group is substituted with 3 to 5 substituents,            -   the heteroaryl group is substituted with 2 to 5                substituents,            -   the alicyclic group is substituted with 3 to 5                substituents,            -   the heterocyclic group is substituted with 3 to 5                substituents, and            -   the substituents on R⁵ are selected from the group                consisting of halogen, lower alkyl, lower alkenyl, lower                alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂,                —NR⁸R¹⁰, lower aryl, heteroaryl, alicyclic, lower                heterocyclic, arylalkyl, heteroarylalkyl, amino,                alkylamino, dialkylamino, diarylalkylamino, oxo, oxa,                perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,                pyridinyl, thiophene, furanyl, indole, indazole,                phosphonates, phosphates, phosphoramides, sulfonates,                sulfones, sulfates, sulphonamides, carbamates, ureas,                thioureas and thioamides, wherein R⁸ and R¹⁰ taken                together optionally form a ring of 3-7 ring atoms and                optionally 1-3 of the ring atoms are heteroatoms                selected from the group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl or —C(O)R⁹;    -   R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹¹        taken together optionally form a ring of 3-7 ring atoms and        optionally 1-3 of the ring atoms are heteroatoms selected from        the group of O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,        lower aryl or lower heteroaryl;    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or        lower heteroaryl;    -   R¹² is hydrogen or lower alkyl;    -   R²¹ is halogen, —OR⁸, —SR⁸ or lower alkyl;    -   R²² is —NR⁸R¹⁰;    -   R²³ is hydrogen, —OH or its keto tautomer, —OR⁸, halogen, —CN,        lower alkyl, lower aryl or —C(O)R⁹;    -   R²⁴ is —CHO, —NH₂, —NO₂ or —NO;    -   R²⁵ is halogen or —OH;    -   R²⁶ is —C(O)NH₂ or C(O)OEt; and    -   R²⁷ is —NH₂, —OH or halogen.

In another aspect, the present invention is directed to pharmaceuticalcompositions comprising the compounds of the invention, in particular,the compounds of Formulae A, I and II, and compounds formed by theprocess of the invention, and their polymorphs, solvates, esters,tautomers, diastereomer, enantiomers, pharmaceutically acceptable saltsand prodrugs thereof, and one or more pharmaceutical excipients, for usein treatment or prevention of diseases that are HSP90-dependent.

In another aspect, the invention features a method of treating anindividual having an HSP90-mediated disorder by administering to theindividual a pharmaceutical composition that comprises apharmaceutically effective amount of a compound of Formula A, I or II,or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,enantiomers pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the invention provides a method for treating anindividual having a disorder selected from the group of inflammatorydiseases, infections, autoimmune disorders, stroke, ischemia, cardiacdisorders, neurological disorders, fibrogenetic disorders, proliferativedisorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolicdiseases, and malignant disease.

In yet another embodiment, the invention provides a method for treatingan individual having a fibrogenetic disorder, such as, for example,scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, livercirrhosis, keloid formation, interstitial nephritis and pulmonaryfibrosis.

In another embodiment, the invention provides a combination therapycomprising the administration of a pharmaceutically effective amount ofa compound of Formula I or Formula II, or a polymorph, solvate, ester,tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt andprodrug thereof, according to any of the preceding aspects orembodiments, and at least one therapeutic agent selected from the groupof cytotoxic agents, anti-angiogenesis agents and anti-neoplasticagents. The anti-neoplastic agent may be selected from the group ofalkylating agents, anti-metabolites, epidophyllotoxins antineoplasticenzymes, topoisomerase inhibitors, procarbazines, mitoxantrones,platinum coordination complexes, biological response modifiers andgrowth inhibitors, hormonal/anti-hormonal therapeutic agents, andhaematopoietic growth factors.

Any of the above described aspects and embodiments of the invention canbe combined where practical.

The individual compounds, methods and compositions prescribed do notpreclude the utilization of other, unspecified steps and agents, andthose of ordinary skill in the art will appreciate that additional stepsand compounds may also be combined usefully within the spirit of variousaspects and embodiments of the invention.

Advantages of the invention depend on the specific aspect and embodimentand may include one or more of: ease of synthesis and/or formulation,solubility, and IC₅₀ relative to previously existing compounds in thesame or different classes of HSP90 inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention, which, upon administrationto a recipient, is capable of providing, either directly or indirectly,a compound of this invention or a pharmaceutically active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowingorally administered compound to be more readily absorbed into blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system).

A “pharmaceutically acceptable salt” may be prepared for any compound ofthe invention having a functionality capable of forming a salt, forexample, an acid or base functionality. Pharmaceutically acceptablesalts may be derived from organic or inorganic acids and bases.Compounds of the invention that contain one or more basic functionalgroups, e.g., amino or alkylamino, are capable of formingpharmaceutically acceptable salts with pharmaceutically acceptableorganic and inorganic acids. These salts can be prepared in situ duringthe final isolation and purification of the compounds of the invention,or by separately reacting a purified compound of the invention in itsfree base form with a suitable organic or inorganic acid, and isolatingthe salt thus formed. Examples of suitable acid salts include acetate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate,2-napthalenesulfonate, nicotinate, nitrate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, salicylate, succinate, sulfate, tartrate, thiocyanate,tosylate and undecampate. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts. See, e.g., Berge et al. “Pharmaceutical Salts”, J. Pharm. Sci.1977, 66:1-19.

Compounds of the present invention that contain one or more acidicfunctional groups are capable of forming pharmaceutically acceptablesalts with pharmaceutically acceptable bases. The term “pharmaceuticallyacceptable salts” in these instances refers to the relatively non-toxic,inorganic and organic base addition salts of compounds of the presentinvention. These salts can likewise be prepared in situ during the finalisolation and purification of the compounds, or by separately reactingthe purified compound in its free acid form with a suitable base, suchas the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation, with ammonia, or with a pharmaceuticallyacceptable organic primary, secondary or tertiary amine. Representativealkali or alkaline earth salts include the lithium, sodium, potassium,calcium, magnesium, and aluminum salts and the like. Illustrativeexamples of some of the bases that can be used include sodium hydroxide,potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄alkyl)₄, and the like. Representative organic amines useful for theformation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroil-soluble or dispersible products may be obtained by suchquaternization. See, for example, Berge et al., supra.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates,phosphate esters, metal salts and sulfonate esters.

Suitable positions for derivatization of the compounds of the inventionto create “prodrugs” include but are not limited, 2-amino substitution.Those of ordinary skill in the art have the knowledge and means toaccomplish this without undue experimentation. Various forms of prodrugsare well known in the art. For examples of such prodrug derivatives,see, e.g.,

-   -   a) Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and        Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985,        vol. 42, p. 309-396;    -   b) Bundgaard, H. “Design and Application of Prodrugs” in A        Textbook ofDrug Design and Development, Krosgaard-Larsen and H.        Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and    -   c) Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38.        Each of which is incorporated herein by reference.

The term “prodrugs” as employed herein includes, but is not limited to,the following groups and combinations of these groups:Amine Prodrugs:

Hydroxy Prodrugs:

-   -   Acyloxyalkyl esters;    -   Alkoxycarbonyloxyalkyl esters;    -   Alkyl esters;    -   Aryl esters; and    -   Disulfide containing esters.

The term “alkyl,” alone or in combination, refers to an optionallysubstituted straight-chain, or optionally substituted branched-chainsaturated hydrocarbon radical having from one to about thirty carbons,more preferably one to twelve carbons. Examples of alkyl radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and thelike. The term “cycloalkyl” embraces cyclic alkyl radicals which includemonocyclic, bicyclic, tricyclic, and higher multicyclic alkyl radicalswherein each cyclic moiety has from three to about eight carbon atoms.Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. A “lower alkyl” is a shorteralkyl, e.g., one containing from one to about six carbon atoms.

The term “alkenyl,” alone or in combination, refers to an optionallysubstituted straight-chain, or optionally substituted branched-chainhydrocarbon radical having one or more carbon-carbon double-bonds andhaving from two to about thirty carbon atoms, more preferably two toabout eighteen carbons. Examples of alkenyl radicals include ethenyl,propenyl, butenyl, 1,3-butadienyl and the like. The term “cycloalkenyl”refers to cyclic alkenyl radicals which include monocyclic, bicyclic,tricyclic, and higher multicyclic alkenyl radicals wherein each cyclicmoiety has from three to about eight carbon atoms. A “lower alkenyl”refers to an alkenyl having from two to about six carbons.

The term “alkynyl,” alone or in combination, refers to an optionallysubstituted straight-chain or optionally substituted branched-chainhydrocarbon radical having one or more carbon-carbon triple-bonds andhaving from two to about thirty carbon atoms, more preferably from twoto about twelve carbon atoms, from two to about six carbon atoms as wellas those having from two to about four carbon atoms. Examples of alkynylradicals include ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and thelike. The term “cycloalkynyl” refers to cyclic alkynyl radicals whichinclude monocyclic, bicyclic, tricyclic, and higher multicyclic alkynylradicals wherein each cyclic moiety has from three to about eight carbonatoms. A “lower alkynyl” refers to an alkynyl having from two to aboutsix carbons.

The terms “heteroalkyl, heteroalkenyl and heteroalkynyl” includeoptionally substituted alkyl, alkenyl and alkynyl structures, asdescribed above, and which have one or more skeletal chain atomsselected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur,phosphorous or combinations thereof.

The term “carbon chain” embraces any alkyl, alkenyl, alkynyl, orheteroalkyl, heteroalkenyl, or heteroalkynyl group, which are linear,cyclic, or any combination thereof. If the chain is part of a linker andthat linker comprises one or more rings as part of the core backbone,for purposes of calculating chain length, the “chain” only includesthose carbon atoms that compose the bottom or top of a given ring andnot both, and where the top and bottom of the ring(s) are not equivalentin length, the shorter distance shall be used in determining the chainlength. If the chain contains heteroatoms as part of the backbone, thoseatoms are not calculated as part of the carbon chain length.

The term “membered ring” can embrace any cyclic structure, includingaromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fusedring systems as described below. The term “membered” is meant to denotethe number of skeletal atoms that constitute the ring. Thus, forexample, pyridine, pyran, and pyrimidine are six-membered rings andpyrrole, tetrahydrofuran, and thiophene are five-membered rings.

The term “aryl,” alone or in combination, refers to an optionallysubstituted aromatic hydrocarbon radical of six to about twenty ringatoms, and includes mono-aromatic rings and fused aromatic ring. A fusedaromatic ring radical contains from two to four fused rings where thering of attachment is an aromatic ring, and the other individual ringswithin the fused ring may be aromatic, heteroaromatic, alicyclic orheterocyclic. Further, the term aryl includes mono-aromatic ring andfused aromatic rings containing from six to about twelve carbon atoms,as well as those containing from six to about ten carbon atoms. Examplesof aryl groups include, without limitation, phenyl, naphthyl, anthryl,chrysenyl, and benzopyrenyl ring systems. The term “lower aryl” refersto an aryl having six to about ten skeletal ring carbons, e.g., phenyland naphthyl ring systems.

The term “heteroaryl” refers to optionally substituted aromatic radicalscontaining from about five to about twenty skeletal ring atoms and whereone or more of the ring atoms is a heteroatom such as, for example,oxygen, nitrogen, sulfur, selenium and phosphorus. The term heteroarylincludes optionally substituted mono-heteroaryl radicals and fusedheteroaryl radicals having at least one heteroatom (e.g., quinoline,benzothiazole). A fused heteroaryl radical may contain from two to fourfused rings and where the ring of attachment is a heteroaromatic ring,the other individual rings within the fused ring system may be aromatic,heteroaromatic, alicyclic or heterocyclic. The term heteroaryl alsoincludes mono-heteroaryls or fused heteroaryls having from five to abouttwelve skeletal ring atoms, as well as those having from five to aboutten skeletal ring atoms. Examples of heteroaryls include, withoutlimitation, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl,indolyl, quinolinyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, benzothiozole, benzimidazole,benzoxazoles, benzothiadiazole, benzoxadiazole, benzotriazole,quinolines, isoquinolines, indoles, purinyl, indolizinyl, thienyl andthe like and their oxides. The term “lower heteroaryl” refers to aheteroaryl having five to about ten skeletal ring atoms, e.g., pyridyl,thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or furanyl.

The term “alicyclic” alone or in combination, refers to an optionallysubstituted saturated or unsaturated nonaromatic hydrocarbon ring systemcontaining from three to about twenty ring atoms. The term alicyclicincludes mono-alicyclic and fused alicyclic radicals. A fused alicyclicmay contain from two to four fused rings where the ring of attachment isan alicyclic ring, and the other individual rings within thefused-alicyclic radical may be aromatic, heteroaromatic, alicyclic andheterocyclic. The term alicyclic also includes mono-alicyclic and fusedalicyclic radicals containing from three to about twelve carbon atoms,as well as those containing from three to about ten carbon atoms.Examples of alicyclics include, without limitation, cyclopropyl,cyclopropenyl, cyclobutyl, cyclopentyl, cyclodecyl, cyclododecyl,cyclopentadienyl, indanyl, and cyclooctatetraenyl ring systems. The term“lower alicyclic” refers to an alicyclic having three to about tenskeletal ring carbons, e.g., cyclopropyl, cyclopropenyl, cyclobutyl,cyclopentyl, decalinyl, and cyclohexyl.

The term “heterocyclic” refers to optionally substituted saturated orunsaturated nonaromatic ring radicals containing from five to abouttwenty ring atoms where one or more of the ring atoms are heteroatomssuch as, for example, oxygen, nitrogen, sulfur, and phosphorus. The termalicyclic includes mono-heterocyclic and fused heterocyclic ringradicals. A fused heterocyclic radical may contain from two to fourfused rings where the attaching ring is a heterocyclic, and the otherindividual rings within the fused heterocyclic radical may be aromatic,heteroaromatic, alicyclic or heterocyclic. The term heterocyclic alsoincludes mono-heterocyclic and fused alicyclic radicals having from fiveto about twelve skeletal ring atoms, as well as those having from fiveto about ten skeletal ring atoms. Example of heterocyclics includewithout limitation, tetrahydrofuranyl, benzodiazepinyl,tetrahydroindazolyl, dihyroquinolinyl, and the like. The term “lowerheterocyclic” refers to a heterocyclic ring system having five to aboutten skeletal ring atoms, e.g., dihydropyranyl, pyrrolidinyl, indolyl,piperidinyl, piperazinyl, and the like.

The term “alkylaryl,” or “araalkyl,” alone or in combination, refers toan aryl radical as defined above in which one H atom is replaced by analkyl radical as defined above, such as, for example, tolyl, xylyl andthe like.

The term “arylalkyl,” alone or in combination, refers to an alkylradical as defined above in which one H atom is replaced by an arylradical as defined above, such as, for example, benzyl, 2-phenylethyland the like.

The term “heteroarylalkyl” refers to an alkyl radical as defined abovein which one H atom is replaced by a heteroaryl radical as definedabove, each of which may be optionally substituted.

The term “alkoxy,” alone or in combination, refers to an alkyl etherradical, alkyl-O-, wherein the term alkyl is defined as above. Examplesof alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “aryloxy,” alone or in combination, refers to an aryl etherradical wherein the term aryl is defined as above. Examples of aryloxyradicals include phenoxy, benzyloxy and the like.

The term “alkylthio,” alone or in combination, refers to an alkyl thioradical, alkyl-S-, wherein the term alkyl is as defined above.

The term “arylthio,” alone or in combination, refers to an aryl thioradical, aryl-S-, wherein the term aryl is as defined above.

The term “heteroarylthio” refers to the group heteroaryl-S-, wherein theterm heteroaryl is as defined above.

The term “acyl” refers to a radical —C(O)R where R includes alkyl,alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkylor heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl,heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroaryl alkylgroups may be optionally substituted.

The term “acyloxy” refers to the ester group —OC(O)R, where R is H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic,arylalkyl, or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl,heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl may beoptionally substituted.

The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl orarylalkyl, wherein the alkyl, aryl and arylalkyl groups may beoptionally substituted.

The term “carboxamido” refers to

-   -   where each of R and R¹ are independently selected from the group        consisting of H, alkyl, aryl, heteroaryl, alicyclic,        heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl,        aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups        may be optionally substituted.

The term “oxo” refers to ═O.

The term “halogen” includes F, Cl, Br and I.

The terms “haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy” includealkyl, alkenyl, alkynyl and alkoxy structures, as described above, thatare substituted with one or more fluorines, chlorines, bromines oriodines, or with combinations thereof.

The terms “perhaloalkyl, perhaloalkyloxy and perhaloacyl” refer toalkyl, alkyloxy and acyl radicals as described above, that all the Hatoms are substituted with fluorines, chlorines, bromines or iodines, orcombinations thereof.

The terms “cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic,heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl, and heteroalkyl”include optionally substituted cycloalkyl, arylalkyl, aryl, heteroaryl,alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl andheteroalkyl groups.

The terms “alkylamino”, refers to the group —NHR where R isindependently selected from alkyl.

The terms “dialkylamino”, refers to the group —NRR′ where R and R′ arealkyls.

The term “sulfide” refers to a sulfur atom covalently linked to twoatoms; the formal oxidation state of said sulfur is (II). The term“thioether” may be used interchangeably with the term “sulfide.”

The term “sulfoxide” refers to a sulfur atom covalently linked to threeatoms, at least one of which is an oxygen atom; the formal oxidationstate of said sulfur atom is (IV).

The term “sulfone” refers to a sulfur atom covalently linked to fouratoms, at least two of which are oxygen atoms; the formal oxidationstate of said sulfur atom is (VI).

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “aryl optionally mono-or di-substituted with an alkyl” means that the alkyl may but need notbe present, or either one alkyl or two may be present, and thedescription includes situations where the aryl is substituted with oneor two alkyls and situations where the aryl is not substituted with analkyl.

“Optionally substituted” groups may be substituted or unsubstituted. Thesubstituents of an “optionally substituted” group may include, withoutlimitation, one or more substituents independently selected from thefollowing groups or designated subsets thereof: lower alkyl, loweralkenyl, lower alkynyl, lower aryl, heteroaryl, alicyclic, heterocyclic,arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino,alkylamino, dialkylamino, diarylalkylamino, alkylthio, arylthio,heteroarylthio, oxo, oxa, carbonyl (—C(O)), carboxyesters (—C(O)OR),carboxamido (—C(O)NH₂), carboxy, acyloxy, —H, halo, —CN, —NO₂, —N₃, —SH,—OH, —C(O)CH₃, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,pyridinyl, thiophene, furanyl, indole, indazole, esters, amides,phosphonates, phosphonic acid, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas,thioamides, thioalkyls. An optionally substituted group may beunsubstituted (e.g., —CH₂CH₃), filly substituted (e.g., —CF₂CF₃),monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH₂CF₃).

The term “pyridine-1-oxy” also means “pyridine-N-oxy.”

Some of the compounds of the present invention may contain one or morechiral centers and therefore may exist in enantiomeric anddiastereomeric forms. The scope of the present invention is intended tocover all isomers per se, as well as mixtures of cis and trans isomers,mixtures of diastereomers and racemic mixtures of enantiomers (opticalisomers) as well. Further, it is possible using well known techniques toseparate the various forms, and some embodiments of the invention mayfeature purified or enriched species of a given enantiomer ordiastereomer.

A “pharmacological composition” refers to a mixture of one or more ofthe compounds described herein, or pharmaceutically acceptable saltsthereof, with other chemical components, such as pharmaceuticallyacceptable carriers and/or excipients. The purpose of a pharmacologicalcomposition is to facilitate administration of a compound to anorganism.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subject agent fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations. A physiologically acceptable carrier should not causesignificant irritation to an organism and does not abrogate thebiological activity and properties of the administered compound.

An “excipient” refers to an inert substance added to a pharmacologicalcomposition to further facilitate administration of a compound. Examplesof excipients include but are not limited to calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils and polyethylene glycols.

A “pharmaceutically effective amount” means an amount which is capableof providing a therapeutic and/or prophylactic effect. The specific doseof compound administered according to this invention to obtaintherapeutic and/or prophylactic effect will, of course, be determined bythe particular circumstances surrounding the case, including, forexample, the specific compound administered, the route ofadministration, the condition being treated, and the individual beingtreated. A typical daily dose (administered in single or divided doses)will contain a dosage level of from about 0.01 mg/kg to about 50-100mg/kg of body weight of an active compound of the invention. Preferreddaily doses generally will be from about 0.05 mg/kg to about 20 mg/kgand ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such asclearance rate, half-life and maximum tolerated dose (MTD) have yet tobe determined but one of ordinary skill in the art can determine theseusing standard procedures.

In some method embodiments, the preferred therapeutic effect is theinhibition, to some extent, of the growth of cells characteristic of aproliferative disorder, e.g., breast cancer. A therapeutic effect willalso normally, but need not, relieve to some extent one or more of thesymptoms other than cell growth or size of cell mass. A therapeuticeffect may include, for example, one or more of 1) a reduction in thenumber of cells; 2) a reduction in cell size; 3) inhibition (i.e.,slowing to some extent, preferably stopping) of cell infiltration intoperipheral organs, e.g., in the instance of cancer metastasis; 3)inhibition (i.e., slowing to some extent, preferably stopping) of tumormetastasis; 4) inhibition, to some extent, of cell growth; and/or 5)relieving to some extent one or more of the symptoms associated with thedisorder.

As used herein, the term IC₅₀ refers to an amount, concentration ordosage of a particular test compound that achieves a 50% inhibition of amaximal response in an assay that measures such response. In some methodembodiments of the invention, the “IC₅₀” value of a compound of theinvention can be greater for normal cells than for cells exhibiting aproliferative disorder, e.g., breast cancer cells. The value depends onthe assay used.

By a “standard” is meant a positive or negative control. A negativecontrol in the context of HER2 expression levels is, e.g., a samplepossessing an amount of HER2 protein that correlates with a normal cell.A negative control may also include a sample that contains no HER2protein. By contrast, a positive control does contain HER2 protein,preferably of an amount that correlates with overexpression as found inproliferative disorders, e.g., breast cancers. The controls may be fromcell or tissue samples, or else contain purified ligand (or absentligand), immobilized or otherwise. In some embodiments, one or more ofthe controls may be in the form of a diagnostic “dipstick.”

By “selectively targeting” is meant affecting one type of cell to agreater extent than another, e.g., in the case of cells with high asopposed to relatively low or normal HER2 levels.

II. Compounds of the Invention

Compounds of the invention and their polymorphs, solvates, esters,tautomers, diastereomers, enantiomers, pharmaceutically acceptable saltsor prodrugs show utility for inhibiting HSP90 and treating and/orpreventing diseases that are HSP90-dependent.

One embodiment of the compounds of the invention is of Formula A:

or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, wherein:

-   -   X¹ and X₂ are the same or different and each is nitrogen or        —CR⁶;    -   X³ is nitrogen or —CR³ wherein R³ is hydrogen, OH, a keto        tautomer, —OR⁸, —CN, halogen, lower alkyl, or —C(O)R⁹;    -   X⁴ is nitrogen or a group CR⁶ when X³ is nitrogen, and X₄ is        —CR⁶R⁷ when X₃ is —CR³;    -   R¹ is halogen, —OR⁸, —SR⁸, or lower alkyl;    -   R² is —NR⁸R¹⁰;    -   R⁴ is —(CH₂)_(n)— wherein n=0-3, —C(O), —C(S), —SO₂—, or —SO₂N—;        and    -   R⁵ is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, each        of which is optionally bi-or tricyclic, and optionally        substituted with H, halogen, lower alkyl, lower alkenyl, lower        alkynyl, lower aryl, lower alicyclic, araalkyl, aryloxyalkyl,        alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N₃,        —SR⁸, —R⁸, —CN, —CO₂R⁹, —NO₂ or —NR⁸R¹⁰;    -   with the provisos that:    -   the compound is not one found or described in one or more of JP        10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,748,177; U.S.        Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO        02/055083; Eur. J. Med. Chem., 1994, 29(1), 3-9; and J. Het.        Chem. 1990, 27(5), 1409;    -   —R⁴R⁵ is not a ribose or derivative thereof, or a sugar or        derivative thereof;    -   —R⁴R⁵ is not a phosphonate or phosphonic acid, or a group        substituted with a phosphonate or phosphonic acid; and    -   when R⁴ is (CH₂)_(n) where n=0 or 1, then R⁴ and R⁵ are not        connected with ‘O’, e.g., —CH₂—O—CH₂— or —CH₂—CH₂ —O—CH₂—.

In one embodiment of the compound, tautomer, pharmaceutically acceptablesalt thereof, or prodrug thereof of Formula A, X₁ and X₂ are the same ordifferent and each is nitrogen or —CR⁶; R¹ is halogen, —OR⁸, —SR⁸, orlower alkyl; R² is —NR⁸R¹⁰; R³ is hydrogen, —OH or keto tautomer, —OR⁸,halogen, —CN, lower alkyl, or —C(O)R⁹; R⁴ is —(CH₂)_(n)— wherein n=0-3,—C(O), —C(S), —SO₂—, or —SO₂N—; and R⁵ is alkyl, aromatic,heteroaromatic, alicyclic, heterocyclic, each of which is optionally bi-or tricyclic, and optionally substituted with H, halogen, lower alkyl,—SR⁸, —OR⁸, —CN, —CO₂R⁹, —NO₂ or —NR⁸R¹⁰; R⁸ is hydrogen, lower alkyl,lower aryl or —(CO)R⁹; R⁹ is lower alkyl, lower aryl, lower heteroaryl,—NR⁸R¹⁰ or OR¹¹; R¹¹ is lower alkyl or lower aryl; and R¹⁰ is hydrogenor lower alkyl.

In one embodiment, the compound, tautomer, pharmaceutically acceptablesalt thereof, or prodrug thereof of Formula A, R¹ is selected fromhalogen, hydroxyl, lower alkoxy, lower thioalkyl and C₁₋₄ alkyl; and R²is —NH₂; and R³ is hydrogen.

In another embodiment, R⁴ is —(CH₂)_(n)—, where n=0-3.

In another embodiment, R′ is selected from halogen, hydroxyl, loweralkoxy, lower thioalkyl or C₁₋₄ alkyl; optionally, R² is —NH₂.

In another embodiment, R⁴ is —CH₂—.

In another embodiment, R⁴ is —(CH₂)_(n)—, wherein n=0-3, R¹ is selectedfrom halogen, hydroxyl, lower alkoxy, lower thioalkyl, and C₁₋₄ alkyl,and R² is optionally NH₂.

In another embodiment, R¹ is halogen, hydroxyl, lower alkoxy, lowerthioalkyl, or C₁₋₄ alkyl; and R² is optionally NH₂, R⁴ is —(CH₂)—, andR⁵ is phenyl, benzyl, or pyridyl, all optionally substituted with H,halogen, lower alkyl, —SR⁸, —OR⁸ (or cyclic ethers such asmethylenedioxy), —CN, —CO₂R⁹, —NO₂, or —NR⁸R¹⁰; R⁸ is hydrogen, loweralkyl, lower aryl or —(CO)R⁹; R⁹ is lower alkyl, lower aryl, lowerheteroaryl, —NR⁸R¹⁰ or —OR¹¹; R¹¹ is lower alkyl or lower aryl; and R¹⁰is hydrogen or lower alkyl.

In another embodiment R¹ is halogen, R² is —NH₂, R⁴ is —CH₂—, R⁶ is H orhalogen, and R⁵ is phenyl optionally substituted with H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, perhaloalkyl, perhaloalkyloxy, —CN,—NO₂, —NH₂ or —CO₂R¹¹.

In another embodiment, R¹ is halogen, R² is —NH₂, R⁴ is —CH₂—, R⁶ is H,and R⁵ is 2-halo-3,5-dimethoxyphenyl optionally substituted with H,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, perhaloalkyl,perhaloalkyloxy, —CN, —NO₂, —NH₂, or —CO₂R¹¹ at the para (4-) position.

In another embodiment, R¹ is chloro, R² is —NH₂, R⁴ is —CH₂—, R⁶is H andR⁵ is 2-chloro-3,4,5-trimethoxyphenyl.

In another embodiment, R¹ is chloro, R² is -NH₂, R⁴ is —CH₂—, R⁶ is Hand R⁵ is 2-bromo-3,4,5-trimethoxyphenyl. In other embodiments, R⁵ isselected from 2-iodo-3,4,5-trimethoxyphenyl,2-fluoro-3,4,5-trimethoxyphenyl, or 2-bromo-3,4,5-trimethoxyphenyl.

Any of the foregoing embodiments can be combined where feasible andappropriate.

In another aspect, the invention provides compounds of Formula A1:

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein

-   -   X¹ and X² are the same or different and each is nitrogen or CR⁶;    -   R¹ is halogen, —OR⁸, —SR⁸ or lower alkyl;    -   R² is —NR⁸R¹⁰;    -   R³ is hydrogen, —OH or keto tautomer, —OR⁸, halogen, —CN, lower        alkyl or —C(O)R⁹;    -   R⁴ is —(CH₂)_(n)— where n=0-3, —C(O), —C(S), —SO2— or —SO₂N—;    -   R⁵ is alkyl, aryl, heteroaryl, alicyclic, heterocyclic, all        optionally bi- or tricyclic, and all optionally substituted with        H, halogen, lower alkyl, —SR⁸, —OR⁸, —CN, —CO₂R⁹, —NO₂ or        —NR⁸R¹⁰;    -   R⁸ is hydrogen, lower alkyl, lower aryl or —(CO)R⁹;    -   R⁹ is lower alkyl, lower aryl, lower heteroaryl, —NR⁸R¹⁰ or        OR¹¹;    -   R¹¹ is lower alkyl or lower aryl; and    -   R¹⁰ is hydrogen or lower alkyl.

In one embodiment of the compounds of Formula A1, or a tautomer,pharmaceutically acceptable salt, or prodrug thereof, R¹ is halogen,hydroxyl, lower alkoxy, lower thioalkyl, or C₁₋₄ alkyl; and R² is NH₂.

In another embodiment of the compounds of Formula A1, or a tautomer,pharmaceutically acceptable salt, or prodrug thereof, R⁴ is —(CH₂)_(n)—,where n=0-3.

In another embodiment of the compounds of Formula A1, or a tautomer,pharmaceutically acceptable salt, or prodrug thereof, R¹ is halogen,hydroxyl, lower alkoxy, lower thioalkyl, or C₁₋₄ alkyl; R² is NH₂; andR⁴ is —(CH₂)_(n)—, wherein n=0-3.

In another embodiment of the compounds of Formula A1, or a tautomer,pharmaceutically acceptable salt thereof, R¹ is halogen; R² is NH₂; andR⁴ is —CH₂—.

Another embodiment of the compounds of the invention is of Formula I:

or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, wherein:

-   -   R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;    -   R² is —NHR⁸;    -   R³ is selected from the group consisting of hydrogen, halogen,        —SR⁸, —OR⁸, —CN, —C(O)R⁹, —CO₂H, —NO₂, —NR⁸R¹⁰, lower alkyl,        lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl,        heteroaryl, alicyclic and heterocyclic, all optionally        substituted,        -   wherein:        -   the aryl, heteroaryl, alicyclic and heterocyclic groups are            optionally mono-, bi- or tri-cyclic;        -   R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ring            atoms and optionally 1-2 of the ring atoms are heteroatoms            selected from the group of O, S and N, and        -   the optional substituents on R³ are selected from the group            consisting of halogen, lower alkyl, lower alkenyl, lower            alkynyl, —SR⁸, —OR⁸, —CN, —C(O)R⁹, —C(O)OH, —NO₂, —NR⁸R¹⁰            lower aryl, lower heteroaryl, lower alicyclic, lower            heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,            dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,            perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene,            furanyl, indole, indazole, phosphonates, phosphates,            phosphoramides, sulfonates, sulfones, sulfates,            sulphonamides, carbamates, ureas, thioureas and thioamides,            wherein R⁸ and R¹⁰ taken together optionally form a ring of            3-7 ring atoms and optionally 1-3 of the ring atoms are            heteroatoms selected from the group of O, S and N;    -   R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;    -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein        -   the aryl group is substituted with 3 to 5 substituents,        -   the heteroaryl group is substituted with 2 to 5            substituents,        -   the alicyclic group is substituted with 3 to 5 substituents,        -   the heterocyclic group is substituted with 3 to 5            substituents, and        -   the substituents on R⁵ are selected from the group            consisting of halogen, lower alkyl, lower alkenyl, lower            alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰            lower aryl, heteroaryl, alicyclic, lower heterocyclic,            arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino,            diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy,            perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,            indole, indazole, phosphonates, phosphates, phosphoramides,            sulfonates, sulfones, sulfates, sulphonamides, carbamates,            ureas, thioureas and thioamides, wherein R⁸ and R¹⁰ taken            together optionally form a ring of 3-7 ring atoms and            optionally 1-3 of the ring atoms are heteroatoms selected            from the group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl or —C(O)R⁹;    -   R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰        taken together optionally form a ring of 3-7 ring atoms and        optionally 1-3 of the ring atoms are heteroatoms selected from        the group of O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,        lower aryl or lower heteroaryl;    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or        lower heteroaryl; and    -   R¹² is hydrogen or lower alkyl.

In one embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is halogen or lower alkyl; R² is —NHR⁸, where R⁸is hydrogen or —C(O)R⁹; R⁵ is aryl or heteroaryl, wherein each of saidaryl and heteroaryl groups is monocyclic or bicyclic.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R² is —NH₂; R³ is selected from hydrogen, halogen,—SR⁸, —OR⁸, —CN, —NR⁸R¹⁰, lower alkyl, lower alkenyl, lower alkynyl,lower perhaloalkyl, lower aryl, lower heteroaryl, lower alicyclic, andlower heterocyclic, wherein R⁸ is hydrogen, lower alkyl, lower alkenyl,lower alkynyl, lower aryl or lower heteroaryl, and wherein R⁸ and R¹⁰when taken together optionally form a ring of 3-7 ring atoms andoptionally 1-3 of the ring atoms are heteroatoms selected from the groupof O, S and N; and R⁵ is aryl or heteroaryl, wherein each of said aryland heteroaryl groups is monocyclic or bicyclic.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is halogen or lower alkyl; R² is —NH₂; R⁴ is—(CH₂)—; and R⁵ is aryl, heteroaryl, alicyclic or heterocyclic, whereineach of said aryl, heteroaryl alicyclic or heterocyclic groups ismonocyclic or bicyclic.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is halogen; R² is —NH₂; R³ is hydrogen, halogen,—SR⁸, —OR⁸, lower alkyl, lower alkenyl, lower alkynyl, lowerperhaloalkyl, lower aryl, lower heteroaryl, or —NR⁸R¹⁰, wherein R⁸ andR¹⁰ taken together optionally form a ring of 3-7 ring atoms andoptionally 1-3 of the ring atoms are heteroatoms selected from the groupof O, S and N; R⁴ is —CH₂—; and R⁵ is aryl or heteroaryl, wherein eachof said aryl and heteroaryl groups is monocyclic or bicyclic.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is halogen; R²is —NH₂; R³ is hydrogen, halogen,—SR⁸, —OR⁸, lower alkyl, lower aryl, lower heteroaryl, or —NR⁸R¹⁰,wherein R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ringatoms and optionally 1-3 of the ring atoms are heteroatoms selected fromthe group of O, S and N; R⁴ is —CH₂—; and R⁵ is aryl or heteroaryl,wherein each of said aryl and heteroaryl groups is monocyclic orbicyclic.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo; and R⁵ is a phenyl having 3to 5 substituents.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo; and R⁵ is a pyridyl having 3to 5 substituents.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo; and R⁵ is an 1-oxy-pyridyl(N-oxy-pyridyl) having 3 to 5 substituents.

It should be understood that any of the foregoing embodiments can becombined where feasible and appropriate.

Another embodiment of the compounds of the invention is of Formula II:

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein:

-   -   R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;    -   R² is —NHR⁸;    -   R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;    -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein        -   the aryl group is substituted with 3 to 5 substituents,        -   the heteroaryl group is substituted with 2 to 5            substituents,        -   the alicyclic group is substituted with 3 to 5 substituents,        -   the heterocyclic group is substituted with 3 to 5            substituents, and        -   the substituents on R⁵ are selected from the group            consisting of halogen, lower alkyl, lower alkenyl, lower            alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰            lower aryl, heteroaryl, alicyclic, lower heterocyclic,            arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino,            diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy,            perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,            indole, indazole, phosphonates, phosphates, phosphoramides,            sulfonates, sulfones, sulfates, sulphonamides, carbamates,            ureas, thioureas and thioamides, wherein R⁸ and R¹⁰ taken            together optionally form a ring of 3-7 ring atoms and            optionally 1-3 of the ring atoms are heteroatoms selected            from the group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl or —C(O)R⁹;    -   R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰        taken together optionally form a ring of 3-7 ring atoms and        optionally 1-3 of the ring atoms are heteroatoms selected from        the group of O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,        lower aryl or lower heteroaryl;    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or        lower heteroaryl;    -   R¹² is hydrogen or lower alkyl; and    -   R¹⁵ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

In one embodiment of the compounds of Formula II, or a polymorph,solvate, ester, tautomer, pharmaceutically acceptable salt or prodrugthereof, R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹; R⁵ is aryl,heteroaryl, alicyclic, or heterocyclic, all optionally mono-, bi- ortri-cyclic; and R⁹ is lower alkyl, lower alkenyl, lower alkynyl, loweraryl or lower heteroaryl.

In another embodiment of the compounds of Formula II, or a polymorph,solvate, ester, tautomer, pharmaceutically acceptable salt or prodrugthereof, R¹ is halogen or lower alkyl; R² is —NHR⁸, where R⁸ is hydrogenor —C(O)R⁹; R⁴ is —(CH₂)—, R⁵ is aryl, heteroaryl, alicyclic, orheterocyclic, all optionally mono-, bi- or tri-cyclic.

In another embodiment of the compounds of Formula II, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NH₂, and R⁵ is aphenyl having 3 to 5 substituents.

In another embodiment of the compounds of Formula II, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NH₂, and R⁵ is apyridyl having 3 to 5 substituents.

In another embodiment of the compounds of Formula II, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NH₂, and R⁵ is an1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.

It should be understood that any of the foregoing embodiments can becombined where feasible and appropriate.

Other embodiment of the compounds of the invention are the compounds, orpolymorphs, solvates, esters, tautomers, pharmaceutically acceptablesalts or prodrugs thereof, prepared by the process comprising:

-   -   reacting a compound of Formula Y and a compound of a Formula Z,        wherein:    -   Y is represented by any of the following formulae:    -   Z is L¹-R⁴—R⁵; wherein:        -   L¹ is halogen, NR⁸R¹⁰ triflate, tosylate, or mesylate;        -   R⁴ is —(CHR¹²)—, —C(O), —C(S), —S(O)—, or —SO₂—;        -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein            -   the aryl group is substituted with 3 to 5 substituents,            -   the heteroaryl group is substituted with 2 to 5                substituents,            -   the alicyclic group is substituted with 3 to 5                substituents,            -   the heterocyclic group is substituted with 3 to 5                substituents, and            -   the substituents on R⁵ are selected from the group                consisting of halogen, lower alkyl, lower alkenyl, lower                alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂,                —NR⁸R¹⁰ lower aryl, heteroaryl, alicyclic, lower                heterocyclic, arylalkyl, heteroarylalkyl, amino,                alkylamino, dialkylamino, diarylalkylamino, oxo, oxa,                perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,                pyridinyl, thiophene, furanyl, indole, indazole,                phosphonates, phosphates, phosphoramides, sulfonates,                sulfones, sulfates, sulphonamides, carbamates, ureas,                thioureas and thioamides, wherein R⁸ and R¹⁰ taken                together optionally form a ring of 3-7 ring atoms and                optionally 1-3 of the ring atoms are heteroatoms                selected from the group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl or —C(O)R⁹;    -   R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰        taken together optionally form a ring of 3-7 ring atoms and        optionally 1-3 of the ring atoms are heteroatoms selected from        the group of O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,        lower aryl or lower heteroaryl;    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or        lower heteroaryl;    -   R¹² is hydrogen or lower alkyl;    -   R²¹ is halogen, —OR⁸, —SR⁸ or lower alkyl;    -   R²² is —NR⁸R¹⁰;    -   R²³ is hydrogen, —OH or its keto tautomer, —OR⁸, halogen, —CN,        lower alkyl, lower aryl or —C(O)R⁹;    -   R²⁴ is —CHO, —NH₂, —NO₂ or —NO;    -   R²⁵ is halogen or —OH;    -   R²⁶ is —C(O)NH₂ or C(O)OEt; and    -   R²⁷ is —NH₂, —OH or halogen.

In one embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, R⁵ is aryl, heteroaryl, alicyclic,or heterocyclic, optionally mono- or bicyclic.

In another embodiment of the compounds of the invention which areprepared by the process of the invention, or a polymorph, solvate,ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, L¹is —Cl, —Br or —NH₂; R⁴ is —CH₂—; and R⁵ is aryl or heteroaryl.

In another embodiment of the compounds of the invention which areprepared by the process of the invention, or a polymorph, solvate,ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Yis a pyrazolopyrimidine.

In another embodiment of the compounds of the invention which areprepared by the process of the invention, or a polymorph, solvate,ester, tautomer, pharmaceutically acceptable salt of prodrug thereof,said reaction is performed in a solvent comprising a member selectedfrom the group of DMF, THF and DMSO.

In another embodiment of the compounds of the invention which areprepared by the process of the invention, or a polymorph, solvate,ester, tautomer, pharmaceutically acceptable salt of prodrug thereof,said reaction is performed in a solvent that comprises DMF.

It should be understood that any of the foregoing embodiments can becombined where feasible and appropriate.

Illustrative species of the compounds of the invention that are based onFormula I, where R²=—NH₂ are described in TABLE 1. Prodrugs which can beemployed by those compounds include, but are not limited to, thoselisted in the Definition section. TABLE 1

Exemplary Compounds of Formula I, R² is = NH₂ No. Ex R¹ R³ R⁴ R⁵ 1 5 ClH CH₂ 3,4,5-Trimethoxyphenyl 2 6 Cl H CH₂2-Chloro-3,4,5-trimethoxyphenyl 3 Cl H CH₂2-Bromo-3,4,5-trimethoxyphenyl 4 Cl H CH₂ 2-Iodo-3,4,5-trimethoxyphenyl5 Cl H CH₂ 2-Fluoro-3,4,5-trimethoxyphenyl 6 Cl H CH₂3,4,5-Trimethylphenyl 7 Cl H CH₂ 2-Chloro-3,4,5-trimethylphenyl 8 Cl HCH₂ 2-Bromo-3,4,5-trimethylphenyl 9 Cl H CH₂2-Iodo-3,4,5-trimethylphenyl 10 Cl H CH₂ 2-Fluoro-3,4,5-trimethylphenyl11 Cl H CH₂ 3,5-Dimethoxy-4-methylphenyl 12 Cl H CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 13 Cl H CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 14 Cl H CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 15 Cl H CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 16 Cl i-pr CH₂3,4,5-Trimethoxyphenyl 17 Cl i-pr CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 18Cl i-pr CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 19 Cl i-pr CH₂2-Iodo-3,4,5-trimethoxyphenyl 20 Cl i-pr CH₂2-Fluoro-3,4,5-trimethoxyphenyl 21 Cl i-pr CH₂ 3,4,5-Trimethyiphenyl 22Cl i-pr CH₂ 2-Chloro-3,4,5-trimethylphenyl 23 Cl i-pr CH₂2-Bromo-3,4,5-trimethylphenyl 24 Cl i-pr CH₂2-Iodo-3,4,5-trimethylphenyl 25 Cl i-pr CH₂2-Fluoro-3,4,5-trimethylphenyl 26 Cl i-pr CH₂3,5-Dimethoxy-4-methylphenyl 27 Cl i-pr CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 28 Cl i-pr CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 29 Cl i-pr CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 30 Cl i-pr CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 31 Cl Et CH₂3,4,5-Trimethoxyphenyl 32 Cl Et CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 33Cl Et CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 34 Cl Et CH₂2-Iodo-3,4,5-trimethoxyphenyl 35 Cl Et CH₂2-Fluoro-3,4,5-trimethoxyphenyl 36 Cl Et CH₂ 3,4,5-Trimethylphenyl 37 ClEt CH₂ 2-Chloro-3,4,5-trimethylphenyl 38 Cl Et CH₂2-Bromo-3,4,5-trimethylphenyl 39 Cl Et CH₂ 2-Iodo-3,4,5-trimethylphenyl40 Cl Et CH₂ 2-Fluoro-3,4,5-trimethylphenyl 41 Cl Et CH₂3,5-Dimethoxy-4-methylphenyl 42 Cl Et CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 43 Cl Et CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 44 Cl Et CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 45 Cl Et CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 46 27 Cl Me CH₂3,4,5-Trimethoxyphenyl 47 Cl Me CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 48Cl Me CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 49 Cl Me CH₂2-Iodo-3,4,5-trimethoxyphenyl 50 Cl Me CH₂2-Fluoro-3,4,5-trimethoxyphenyl 51 Cl Me CH₂ 3,4,5-Trimethylphenyl 52 ClMe CH₂ 2-Chloro-3,4,5-trimethylphenyl 53 Cl Me CH₂2-Bromo-3,4,5-trimethylphenyl 54 Cl Me CH₂ 2-Iodo-3,4,5-trimethylphenyl55 Cl Me CH₂ 2-Fluoro-3,4,5-trimethylphenyl 56 Cl Me CH₂3,5-Dimethoxy-4-methylphenyl 57 Cl Me CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 58 Cl Me CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 59 Cl Me CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 60 Cl Me CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 61 Cl Ph CH₂3,4,5-Trimethoxyphenyl 62 Cl Ph CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 63Cl Ph CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 64 Cl Ph CH₂2-Iodo-3,4,5-trimethoxyphenyl 65 Cl Ph CH₂2-Fluoro-3,4,5-trimethoxyphenyl 66 Cl Ph CH₂ 3,4,5-Trimethylphenyl 67 ClPh CH₂ 2-Chloro-3,4,5-trimethylphenyl 68 Cl Ph CH₂2-Bromo-3,4,5-trimethylphenyl 69 Cl Ph CH₂ 2-Iodo-3,4,5-trimethylphenyl70 Cl Ph CH₂ 2-Fluoro-3,4,5-trimethylphenyl 71 Cl Ph CH₂3,5-Dimethoxy-4-methylphenyl 72 Cl Ph CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 73 Cl Ph CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 74 Cl Ph CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 75 Cl Ph CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 76 Cl 2-Py CH₂3,4,5-Trimethoxyphenyl 77 Cl 2-Py CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 78Cl 2-Py CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 79 Cl 2-Py CH₂2-Iodo-3,4,5-trimethoxyphenyl 80 Cl 2-Py CH₂ 2-Fluoro-3,4,5-trimethoxyphenyl 81 Cl 2-Py CH₂ 3,4,5-Trimethylphenyl 82 Cl 2-Py CH₂2-Chloro-3,4,5-trimethylphenyl 83 Cl 2-Py CH₂2-Bromo-3,4,5-trimethylphenyl 84 Cl 2-Py CH₂2-Iodo-3,4,5-trimethylphenyl 85 Cl 2-Py CH₂2-Fluoro-3,4,5-trimethylphenyl 86 Cl 2-Py CH₂3,5-Dimethoxy-4-methylphenyl 87 Cl 2-Py CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 88 Cl 2-Py CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 89 Cl 2-Py CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 90 Cl 2-Py CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 91 Cl Me CH₂3,4,5-Trimethoxyphenyl 92 Cl Me CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 93Cl Me CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 94 Cl Me CH₂2-Iodo-3,4,5-trimethoxyphenyl 95 Cl Me CH₂2-Fluoro-3,4,5-trimethoxyphenyl 96 Cl Ph CH₂ 3,4,5-Trimethylphenyl 97 ClPh CH₂ 2-Chloro-3,4,5-trimethylphenyl 98 Cl Ph CH₂2-Bromo-3,4,5-trimethylphenyl 99 Cl Ph CH₂ 2-Iodo-3,4,5-trimethylphenyl100 Cl Ph CH₂ 2-Fluoro-3,4,5-trimethylphenyl 101 Cl Ph CH₂3,5-Dimethoxy-4-methylphenyl 102 Cl Ph CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 103 Cl Ph CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 104 Cl Ph CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 105 Cl Pr CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 106 Cl Pr CH₂3,5-Dimethoxy-4-methylphenyl 107 Cl Pr CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 108 Cl Pr CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 109 Cl Pr CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 110 Cl Pr CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 111 Cl Pr CH₂3,4,5-Trimethoxyphenyl 112 Cl Pr CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 113Cl Pr CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 114 Cl Pr CH₂2-Iodo-3,4,5-trimethoxyphenyl 115 Cl Pr CH₂2-Fluoro-3,4,5-trimethoxyphenyl 116 Cl Pr CH₂ 3,4,5-Trimethylphenyl 117Cl Pr CH₂ 2-Chloro-3,4,5-trimethylphenyl 118 Cl Pr CH₂2-Bromo-3,4,5-trimethylphenyl 119 Cl Pr CH₂ 2-Iodo-3,4,5-trimethylphenyl120 Cl Pr CH₂ 2-Fluoro-3,4,5-trimethylphenyl 121 Cl Pr CH₂3,5-Dimethoxy-4-methylphenyl 122 Cl Pr CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 123 Cl Pr CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 124 Cl Pr CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 125 Cl Pr CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 126 Br H CH₂3,4,5-Trimethoxyphenyl 127 Br H CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 128Br H CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 129 Br H CH₂2-Iodo-3,4,5-trimethoxyphenyl 130 Br H CH₂2-Fluoro-3,4,5-trimethoxyphenyl 131 Br H CH₂ 3,4,5-Trimethylphenyl 132Br H CH₂ 2-Chloro-3,4,5-trimethylphenyl 133 Br H CH₂2-Bromo-3,4,5-trimethylphenyl 134 Br H CH₂ 2-Iodo-3,4,5-trimethylphenyl135 Br H CH₂ 2-Fluoro-3,4,5-trimethylphenyl 136 Br H CH₂3,5-Dimethoxy-4-methylphenyl 137 Br H CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 138 Br H CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 139 Br H CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 140 Br H CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 141 Cl i-Bu CH₂3,4,5-Trimethoxyphenyl 142 Cl i-Bu CH₂ 2-Chloro-3,4,5-trimethoxyphenyl143 Cl i-Bu CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 144 Cl i-Bu CH₂2-Iodo-3,4,5-trimethoxyphenyl 145 Cl i-Bu CH₂2-Fluoro-3,4,5-trimethoxyphenyl 146 Cl i-Bu CH₂ 3,4,5-Trimethylphenyl147 Cl i-Bu CH₂ 2-Chloro-3,4,5-trimethylphenyl 148 Cl i-Bu CH₂2-Bromo-3,4,5-trimethylphenyl 149 Cl i-Bu CH₂2-Iodo-3,4,5-trimethylphenyl 150 Cl i-Bu CH₂2-Fluoro-3,4,5-trimethylphenyl 151 Cl i-Bu CH₂3,5-Dimethoxy-4-methylphenyl 152 Cl i-Bu CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 153 Cl i-Bu CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 154 Cl i-Bu CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 155 Cl i-Bu CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 156 Cl CN CH₂3,4,5-Trimethoxyphenyl 157 Cl CN CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 158Cl CN CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 159 Cl CN CH₂2-Iodo-3,4,5-trimethoxyphenyl 160 Cl CN CH₂ 3,4,5-Trimethoxyphenyl 161Cl CN CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 162 Cl CN CH₂2-Bromo-3,4,5-trimethoxyphenyl 163 Cl CN CH₂2-Iodo-3,4,5-trimethoxyphenyl 164 Cl CN CH₂2-Fluoro-3,4,5-trimethoxyphenyl 165 Cl CN CH₂ 3,4,5-Trimethylphenyl 166Cl CN CH₂ 2-Chloro-3,4,5-trimethylphenyl 167 Cl CN CH₂2-Bromo-3,4,5-trimethylphenyl 168 Cl CN CH₂ 2-Iodo-3,4,5-trimethylphenyl169 Cl CN CH₂ 2-Fluoro-3,4,5-trimethylphenyl 170 Cl CN CH₂3,5-Dimethoxy-4-methylphenyl 171 Cl CN CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 172 Cl CN CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 173 Cl CN CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 174 Cl CN CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 175 Cl Cl CH₂3,4,5-Trimethoxyphenyl 176 Cl Cl CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 177Cl Cl CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 178 Cl Cl CH₂2-Iodo-3,4,5-trimethoxyphenyl 179 Cl Cl CH₂2-Fluoro-3,4,5-trimethoxyphenyl 180 Cl Cl CH₂ 3,4,5-Trimethylphenyl 181Cl Cl CH₂ 2-Chloro-3,4,5-trimethylphenyl 182 Cl Cl CH₂2-Bromo-3,4,5-trimethylphenyl 183 Cl Cl CH₂ 2-Iodo-3,4,5-trimethylphenyl184 Cl Cl CH₂ 2-Fluoro-3,4,5-trimethylphenyl 185 Cl Cl CH₂3,5-Dimethoxy-4-methylphenyl 186 Cl Cl CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 187 Cl Cl CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 188 Cl Cl CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 189 Cl Cl CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 190 Cl Br CH₂3,4,5-Trimethoxyphenyl 191 Cl Br CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 192Cl Br CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 193 Cl Br CH₂2-Iodo-3,4,5-trimethoxyphenyl 194 Cl Br CH₂2-Fluoro-3,4,5-trimethoxyphenyl 195 Cl Br CH₂ 3,4,5-Trimethylphenyl 196Cl Br CH₂ 2-Chloro-3,4,5-trimethylphenyl 197 Cl Br CH₂2-Bromo-3,4,5-trimethylphenyl 198 Cl Br CH₂ 2-Iodo-3,4,5-trimethylphenyl199 Cl Br CH₂ 2-Fluoro-3,4,5-trimethylphenyl 200 Cl Br CH₂3,5-Dimethoxy-4-methylphenyl 201 Cl Br CH₂ 2-Chloro-3,5-dimethoxy-4-methylphenyl 202 Cl Br CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 203 Cl Br CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 204 Cl Br CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 205 Cl I CH₂3,4,5-Trimethoxyphenyl 206 Cl I CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 207Cl I CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 208 Cl I CH₂2-Iodo-3,4,5-trimethoxyphenyl 209 Cl I CH₂2-Fluoro-3,4,5-trimethoxyphenyl 210 Cl I CH₂ 3,4,5-Trimethylphenyl 211Cl I CH₂ 2-Chloro-3,4,5-trimethylphenyl 212 Cl I CH₂2-Bromo-3,4,5-trimethylphenyl 213 Cl I CH₂ 2-Iodo-3,4,5-trimethylphenyl214 Cl I CH₂ 2-Fluoro-3,4,5-trimethylphenyl 215 Cl I CH₂3,5-Dimethoxy-4-methylphenyl 216 Cl I CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 217 Cl I CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 218 Cl I CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 219 Cl I CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 220 Cl CH₂—NMe₂ CH₂3,4,5-Trimethoxyphenyl 221 Cl CH₂—NMe₂ CH₂2-Chloro-3,4,5-trimethoxyphenyl 222 Cl CH₂—NMe₂ CH₂2-Bromo-3,4,5-trimethoxyphenyl 223 Cl CH₂—NMe₂ CH₂2-Iodo-3,4,5-trimethoxyphenyl 224 Cl CH₂—NMe₂ CH₂2-Fluoro-3,4,5-trimethoxyphenyl 225 Cl CH₂—NMe₂ CH₂3,4,5-Trimethylphenyl 226 Cl CH₂—NMe₂ CH₂ 2-Chloro-3,4,5-trimethylphenyl227 Cl CH₂—NMe₂ CH₂ 2-Bromo-3,4,5-trimethyiphenyl 228 Cl CH₂—NMe₂ CH₂2-Iodo-3,4,5-trimethylphenyl 229 Cl CH₂—NMe₂ CH₂2-Fluoro-3,4,5-trimethylphenyl 230 Cl CH₂—NMe₂ CH₂3,5-Dimethoxy-4-methylphenyl 231 Cl CH₂—NMe₂ CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 232 Cl CH₂—NMe₂ CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 233 Cl CH₂—NMe₂ CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 234 Cl CH₂—NMe₂ CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 235 Cl 3-Py CH₂3,4,5-Trimethoxyphenyl 236 Cl 3-Py CH₂ 2-Chloro-3,4,5-trimethoxyphenyl237 Cl 3-Py CH₂ 2-Bromo-3,4,5-trimethoxyphenyl 238 Cl 3-Py CH₂2-Iodo-3,4,5-trimethoxyphenyl 239 Cl 3-Py CH₂2-Fluoro-3,4,5-trimethoxyphenyl 240 7 Cl H CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 241 10 Cl H CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 242 Cl H CH₂6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 243 8 Cl H CH₂6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 244 14 Cl H CH₂3,5-Dimethyl-4-bromopyridin-2-yl 245 15 Cl H CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 246 9 Cl H CH₂3,5-Dimethyl-4-chloropyridin-2-yl 247 Cl H CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 248 Cl H CH₂3,5-Dimethyl-4-iodopyridin-2-yl 249 Cl H CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 250 Cl H CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 251 Cl H CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 252 Cl H CH₂3,4,5-Trimethyl-pyridin-2-yl 253 Cl H CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 254 Cl H CH₂4,5,6-Trimethoxypyridin-2-yl 255 Cl H CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 256 Cl H CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 257 Cl H CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 258 Cl H CH₂3,4,5-Trimethoxy-pyridin-2-yl 259 Cl H CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 260 Cl H CH₂3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 261 Cl H CH₂3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 262 Cl H CH₂4,5,6-Trimethyl-pyridin-2-yl 263 Cl H CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 264 Cl H CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 265 Cl H CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 266 Cl H CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 267 Cl H CH₂4,6-Dimethyl-5-bromopyridin-3-yl 268 Cl H CH₂4,6-Dimethyl-5-chloropyridin-3-yl 269 Cl H CH₂5,6-Dimethyl-4-bromopyridin-3-yl 270 Cl H CH₂5,6-Dimethyl-4-chloropyridin-3-yl 271 Cl H CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 272 Cl H CH₂2,6-Dimethyl-pyridin-4-yl 273 Cl H CH₂ 2,3,6-Trimethyl-pyridin-4-yl 274Cl H CH₂ 2,3,6-Trimethoxy-pyridin-4-yl 275 Cl H CH₂2,6-Dimethyl-3-bromopyridin-4-yl 276 Cl H CH₂2,6-Dimethyl-3-chloropyridin-4-yl 277 Cl H CH₂2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 278 Cl H CH₂2,6-Dimethyl-1-oxy-pyridin-4-yl 279 Cl H CH₂2,3,6-Trimethyl-1-oxy-pyridin-4-yl 280 Cl H CH₂2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 281 Cl H CH₂2,6-Dimethyl-3-bromol-oxy-pyridin-4-yl 282 Cl H CH₂2,6-Dimethyl-3-chlorol-oxy-pyridin-4-yl 283 Cl H CH₂4,6-Dimethyl-5-iodopyridin-3-yl 284 Cl H CH₂3,5-Dimethyl-4-aminopyridin-2-yl 285 31 Cl i-pr CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 286 Cl i-pr CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 287 Cl i-pr CH₂6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 288 Cl i-pr CH₂6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 289 Cl i-pr CH₂3,5-Dimethyl-4-bromopyridin-2-yl 290 Cl i-pr CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 291 Cl i-pr CH₂3,5-Dimethyl-4-chloropyridin-2-yl 292 Cl i-pr CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 293 Cl i-pr CH₂3,5-Dimethyl-4-iodopyridin-2-yl 294 Cl i-pr CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 295 Cl i-pr CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 296 Cl i-pr CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 297 Cl i-pr CH₂3,4,5-Trimethyl-pyridin-2-yl 298 Cl i-pr CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 299 Cl i-pr CH₂4,5,6-Trimethoxypyridin-2-yl 300 Cl i-pr CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 301 Cl i-pr CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 302 Cl i-pr CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 303 Cl i-pr CH₂3,4,5-Trimethoxy-pyridin-2-yl 304 Cl i-pr CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 305 Cl i-pr CH₂3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 306 Cl i-pr CH₂3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 307 Cl i-pr CH₂4,5,6-Trimethyl-pyridin-2-yl 308 Cl i-pr CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 309 Cl i-pr CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 310 Cl i-pr CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 311 Cl i-pr CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 312 Cl i-pr CH₂4,6-Dimethyl-5-bromopyridin-3-yl 313 Cl i-pr CH₂4,6-Dimethyl-5-chloropyridin-3-yl 314 Cl i-pr CH₂5,6-Dimethyl-4-bromopyridin-3-yl 315 Cl i-pr CH₂5,6-Dimethyl-4-chloropyridin-3-yl 316 Cl i-pr CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 317 Cl i-pr CH₂2,6-Dimethyl-pyridin-4-yl 318 Cl i-pr CH₂ 2,3,6-Trimethyl-pyridin-4-yl319 Cl i-pr CH₂ 2,3 ,6-Trimethoxy-pyridin-4-yl 320 Cl i-pr CH₂2,6-Dimethyl-3-bromopyridin-4-yl 321 Cl i-pr CH₂2,6-Dimethyl-3-chloropyridin-4-yl 322 Cl i-pr CH₂2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 323 Cl i-pr CH₂2,6-Dimethyl-1-oxy-pyridin-4-yl 324 Cl i-pr CH₂2,3,6-Trimethyl-1-oxy-pyridin-4-yl 325 Cl i-pr CH₂ 2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 326 Cl i-pr CH₂2,6-Dimethyl-3-bromol-oxy-pyridin-4-yl 327 Cl i-pr CH₂2,6-Dimethyl-3-chlorol-oxy-pyridin-4-yl 328 Cl i-pr CH₂4,6-Dimethyl-5-iodopyridin-3-yl 329 Cl i-pr CH₂3,5-Dimethyl-4-aminopyridin-2-yl 330 23 Cl Me CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 331 Cl Me CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 332 28 Cl Me CH₂3,5-Dimethyl-4-bromopyridin-2-yI 333 24 Cl Me CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 334 26 Cl Me CH₂3,5-Dimethyl-4-chloropyridin-2-yl 335 25 Cl Me CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 336 Cl Me CH₂3,5-Dimethyl-4-iodopyridin-2-yl 337 Cl Me CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 338 Cl Me CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 339 Cl Me CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 340 Cl Me CH₂3,4,5-Trimethyl-pyridin-2-yl 341 Cl Me CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 342 Cl Me CH₂4,5,6-Trimethoxypyridin-2-yl 343 Cl Me CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 344 Cl Me CH₂3,4,5-Trimethoxy-pyridin-2-yl 345 Cl Me CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 346 Cl Me CH₂4,5,6-Trimethyl-pyridin-2-yl 347 Cl Me CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 348 Cl Me CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 349 Cl Me CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 350 Cl Me CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 351 Cl Me CH₂4,6-Dimethyl-5-bromopyridin-3-yl 352 Cl Me CH₂4,6-Dimethyl-5-chloropyridin-3-yl 353 Cl Me CH₂5,6-Dimethyl-4-bromopyridin-3-yl 354 Cl Me CH₂5,6-Dimethyl-4-chloropyridin-3-yl 355 Cl Me CH₂ 2,6-Dimethyl-3-methoxypyridin-4-yl 356 Cl Me CH₂ 2,6-Dimethyl-pyridin-4-yl 357 Cl MeCH₂ 2,3,6-Trimethyl-pyridin-4-yl 358 Cl Me CH₂2,3,6-Trimethoxy-pyridin-4-yl 359 Cl Me CH₂2,6-Dimethyl-3-bromopyridin-4-yl 360 Cl Me CH₂2,6-Dimethyl-3-chloropyridin-4-yl 361 Cl Me CH₂4,6-Dimethyl-5-iodopyridin-3-yl 362 Cl Me CH₂3,5-Dimethyl-4-aminopyridin-2-yl 363 29 Cl Et CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 364 Cl Et CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 365 Cl Et CH₂3,5-Dimethyl-4-bromopyridin-2-yl 366 Cl Et CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 367 30 Cl Et CH₂3,5-Dimethyl-4-chloropyridin-2-yl 368 Cl Et CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 369 Cl Et CH₂3,5-Dimethyl-4-iodopyridin-2-yl 370 Cl Et CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 371 Cl Et CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 372 Cl Et CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 373 Cl Et CH₂3,4,5-Trimethyl-pyridin-2-yl 374 Cl Et CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 375 Cl Et CH₂4,5,6-Trimethoxypyridin-2-yl 376 Cl Et CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 377 Cl Et CH₂3,4,5-Trimethoxy-pyridin-2-yl 378 Cl Et CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 379 Cl Et CH₂4,5,6-Trimethyl-pyridin-2-yl 380 Cl Et CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 381 Cl Et CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 382 Cl Et CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 383 Cl Et CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 384 Cl Et CH₂4,6-Dimethyl-5-bromopyridin-3-yl 385 Cl Et CH₂4,6-Dimethyl-5-chloropyridin-3-yl 386 Cl Et CH₂5,6-Dimethyl-4-bromopyridin-3-yl 387 Cl Et CH₂5,6-Dimethyl-4-chloropyridin-3-yl 388 Cl Et CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 389 Cl Et CH₂2,6-Dimethyl-pyridin-4-yl 390 Cl Et CH₂ 2,3,6-Trimethyl-pyridin-4-yl 391Cl Et CH₂ 2,3,6-Trimethoxy-pyridin-4-yl 392 Cl Et CH₂2,6-Dimethyl-3-bromopyridin-4-yl 393 Cl Et CH₂2,6-Dimethyl-3-chloropyridin-4-yl 394 Cl Et CH₂4,6-Dimethyl-5-iodopyridin-3-yl 395 Cl Et CH₂3,5-Dimethyl-4-aminopyridin-2-yl 396 Cl 2-Py CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 397 Cl 2-Py CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 398 Cl 2-Py CH₂3,5-Dimethyl-4-bromopyridin-2-yl 399 Cl 2-Py CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 400 Cl 2-Py CH₂3,5-Dimethyl-4-chloropyridin-2-yl 401 Cl 2-Py CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 402 Cl 2-Py CH₂3,5-Dimethyl-4-iodopyridin-2-yl 403 Cl 2-Py CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 404 Cl 2-Py CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 405 Cl 2-Py CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 406 Cl 2-Py CH₂3,4,5-Trimethyl-pyridin-2-yl 407 Cl 2-Py CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 408 Cl 2-Py CH₂4,5,6-Trimethoxypyridin-2-yl 409 Cl 2-Py CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 410 Cl 2-Py CH₂3,4,5-Trimethoxy-pyridin-2-yl 411 Cl 2-Py CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 412 Cl 2-Py CH₂4,5,6-Trimethyl-pyridin-2-yl 413 Cl 2-Py CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 414 Cl 2-Py CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 415 Cl 2-Py CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 416 Cl 2-Py CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 417 Cl 2-Py CH₂4,6-Dimethyl-5-bromopyridin-3-yl 418 Cl 2-Py CH₂4,6-Dimethyl-5-chloropyridin-3-yl 419 Cl 2-Py CH₂5,6-Dimethyl-4-bromopyridin-3-yl 420 Cl 2-Py CH₂5,6-Dimethyl-4-chloropyridin-3-yl 421 Cl 2-Py CH₂ 2,6-Dimethyl-3-methoxypyridin-4-yl 422 Cl 2-Py CH₂ 2,6-Dimethyl-pyridin-4-yl 423 Cl2-Py CH₂ 2,3,6-Trimethyl-pyridin-4-yl 424 Cl 2-Py CH₂2,3,6-Trimethoxy-pyridin-4-yl 425 Cl 2-Py CH₂ 2,6-Dimethyl-3-bromopyridin-4-yl 426 Cl 2-Py CH₂ 2,6-Dimethyl-3-chloropyridin-4-yl 427Cl 2-Py CH₂ 4,6-Dimethyl-5-iodopyridin-3-yl 428 Cl 2-Py CH₂3,5-Dimethyl-4-aminopyridin-2-yl 429 32 Cl Ph CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 430 Cl Ph CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 431 34 Cl Ph CH₂3,5-Dimethyl-4-bromopyridin-2-yl 432 Cl Ph CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 433 33 Cl Ph CH₂3,5-Dimethyl-4-chloropyridin-2-yl 434 35 Cl Ph CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 435 Cl Ph CH₂3,5-Dimethyl-4-iodopyridin-2-yl 436 Cl Ph CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 437 Cl Ph CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 438 Cl Ph CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 439 Cl Ph CH₂3,4,5-Trimethyl-pyridin-2-yl 440 Cl Ph CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 441 Cl Ph CH₂4,5,6-Trimethoxypyridin-2-yl 442 Cl Ph CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 443 Cl Ph CH₂3,4,5-Trimethoxy-pyridin-2-yl 444 Cl Ph CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 445 Cl Ph CH₂4,5,6-Trimethyl-pyridin-2-yl 446 Cl Ph CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 447 Cl Ph CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 448 Cl Ph CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 449 Cl Ph CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 450 Cl Ph CH₂4,6-Dimethyl-5-bromopyridin-3-yl 451 Cl Ph CH₂4,6-Dimethyl-5-chloropyridin-3-yl 452 Cl Ph CH₂5,6-Dimethyl-4-bromopyridin-3-yl 453 Cl Ph CH₂5,6-Dimethyl-4-chloropyridin-3-yl 454 Cl Ph CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 455 Cl Ph CH₂2,6-Dimethyl-pyridin-4-yl 456 Cl Ph CH₂ 2,3,6-Trimethyl-pyridin-4-yl 457Cl Ph CH₂ 2,3,6-Trimethoxy-pyridin-4-yl 458 Cl Ph CH₂2,6-Dimethyl-3-bromopyridin-4-yl 459 Cl Ph CH₂2,6-Dimethyl-3-chloropyridin-4-yl 460 Cl Ph CH₂4,6-Dimethyl-5-iodopyridin-3-yl 461 Cl Ph CH₂3,5-Dimethyl-4-aminopyridin-2-yl 462 Cl 3-Py CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 463 Cl 3-Py CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 464 Cl 3-Py CH₂3,5-Dimethyl-4-bromopyridin-2-yl 465 Cl 3-Py CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 466 Cl 3-Py CH₂3,5-Dimethyl-4-chloropyridin-2-yl 467 Cl 3-Py CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 468 Cl 3-Py CH₂3,5-Dimethyl-4-iodopyridin-2-yl 469 Cl 3-Py CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 470 Cl 3-Py CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 471 Cl 3-Py CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 472 Cl 3-Py CH₂3,4,5-Trimethyl-pyridin-2-yl 473 Cl 3-Py CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 474 Cl 3-Py CH₂4,5,6-Trimethoxypyridin-2-yl 475 Cl 3-Py CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 476 Cl 3-Py CH₂3,4,5-Trimethoxy-pyridin-2-yl 477 Cl 3-Py CH₂3,4,5-Tnmethoxy-1-oxypyridin-2-yl 478 Cl 3-Py CH₂4,5,6-Trimethyl-pyridin-2-yl 479 Cl 3-Py CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 480 Cl 3-Py CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 481 Cl 3-Py CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 482 Cl 3-Py CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 483 Cl 3-Py CH₂4,6-Dimethyl-5-bromopyridin-3-yl 484 Cl 3-Py CH₂4,6-Dimethyl-5-chloropyridin-3-yl 485 Cl 3-Py CH₂5,6-Dimethyl-4-bromopyridin-3-yl 486 Cl 3-Py CH₂5,6-Dimethyl-4-chloropyridin-3-yl 487 Cl 3-Py CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 488 Cl 3-Py CH₂2,6-Dimethyl-pyridin-4-yl 489 Cl 3-Py CH₂ 2,3,6-Trimethyl-pyridin-4-yl490 Cl 3-Py CH₂ 2,3,6-Trimethoxy-pyridin-4-yl 491 Cl 3-Py CH₂2,6-Dimethyl-3-bromopyridin-4-yl 492 Cl 3-Py CH₂2,6-Dimethyl-3-chloropyridin-4-yl 493 Cl 3-Py CH₂4,6-Dimethyl-5-iodopyridin-3-yl 494 Cl 3-Py CH₂3,5-Dimethyl-4-aminopyridin-2-yl 495 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 496 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 497 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-bromopyridin-2-yl 498 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 499 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-chloropyridin-2-yl 500 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 501 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-iodopyridin-2-yl 502 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 503 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 504 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 505 Cl CH₂—NMe₂ CH₂3,4,5-Trimethyl-pyridin-2-yl 506 Cl CH₂—NMe₂ CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 507 Cl CH₂—NMe₂ CH₂4,5,6-Trimethoxypyridin-2-yl 508 Cl CH₂—NMe₂ CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 509 Cl CH₂—NMe₂ CH₂3,4,5-Trimethoxy-pyridin-2-yl 510 Cl CH₂—NMe₂ CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 511 Cl CH₂—NMe₂ CH₂4,5,6-Trimethyl-pyridin-2-yl 512 Cl CH₂—NMe₂ CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 513 Cl CH₂—NMe₂ CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 514 Cl CH₂—NMe₂ CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 515 Cl CH₂—NMe₂ CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 516 Cl CH₂—NMe₂ CH₂4,6-Dimethyl-5-bromopyridin-3-yI 517 Cl CH₂—NMe₂ CH₂4,6-Dimethyl-5-chloropyridin-3-yl 518 Cl CH₂—NMe₂ CH₂5,6-Dimethyl-4-bromopyridin-3-yl 519 Cl CH₂—NMe₂ CH₂ 5,6-Dimethyl-4-chloropyridin-3-yl 520 Cl CH₂—NMe₂ CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 521 Cl CH₂—NMe₂ CH₂2,6-Dimethyl-pyridin-4-yl 522 Cl CH₂—NMe₂ CH₂2,3,6-Trimethyl-pyridin-4-yl 523 Cl CH₂—NMe₂ CH₂2,3,6-Trimethoxy-pyridin-4-yl 524 Cl CH₂—NMe₂ CH₂2,6-Dimethyl-3-bromopyridin-4-yl 525 Cl CH₂—NMe₂ CH₂2,6-Dimethyl-3-chloropyridin-4-yl 526 Cl CH₂—NMe₂ CH₂4,6-Dimethyl-5-iodopyridin-3-yl 527 Cl CH₂—NMe₂ CH₂3,5-Dimethyl-4-aminopyridin-2-yl 528 Cl 2-furanyl CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 529 Cl 2-furanyl CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 530 Cl 2-furanyl CH₂3,5-Dimethyl-4-bromopyridin-2-yl 531 Cl 2-furanyl CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 532 Cl 2-furanyl CH₂3,5-Dimethyl-4-chloropyridin-2-yl 533 Cl 2-furanyl CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 534 Cl 2-furanyl CH₂3,5-Dimethyl-4-iodopyridin-2-yl 536 Cl 2-furanyl CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 537 Cl 2-furanyl CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 538 Cl 2-furanyl CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 539 Cl 2-furanyl CH₂3,4,5-Trimethyl-pyridin-2-yl 540 Cl 2-furanyl CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 541 Cl 2-furanyl CH₂4,5,6-Triinethoxypyridin-2-yl 542 Cl 2-furanyl CH₂ 4,5,6-Trimethoxy-1-oxypyridin-2-yl 543 Cl 2-furanyl CH₂3,4,5-Trimethoxy-pyridin-2-yl 544 Cl 2-furanyl CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 545 Cl 2-furanyl CH₂4,5,6-Trimethyl-pyridin-2-yl 546 Cl 2-furanyl CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 547 Cl 2-furanyl CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 548 Cl 2-furanyl CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 549 Cl 2-furanyl CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 550 Cl 2-furanyl CH₂4,6-Dimethyl-5-bromopyridin-3-yl 551 Cl 2-furanyl CH₂4,6-Dimethyl-5-chloropyridin-3-yl 552 Cl 2-furanyl CH₂5,6-Dimethyl-4-bromopyridin-3-yl 553 Cl 2-furanyl CH₂5,6-Dimethyl-4-chloropyridin-3-yl 554 Cl 2-furanyl CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 555 Cl 2-furanyl CH₂2,6-Dimethyl-pyridin-4-yl 556 Cl 2-furanyl CH₂2,3,6-Trimethyl-pyridin-4-yl 557 Cl 2-furanyl CH₂2,3,6-Trimethoxy-pyridin-4-yl 558 Cl 2-furanyl CH₂2,6-Dimethyl-3-bromopyridin-4-yl 559 Cl 2-furanyl CH₂2,6-Dimethyl-3-chloropyridin-4-yl 560 Cl 2-furanyl CH₂3,5-Dimethyl-4-aminopyridin-2-yl 561 Cl Cl CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 562 Cl Cl CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 563 Cl Cl CH₂3,5-Dimethyl-4-bromopyridin-2-yl 564 Cl Cl CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 565 Cl Cl CH₂3,5-Dimethyl-4-chloropyridin-2-yl 566 Cl Cl CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 567 Cl Cl CH₂3,5-Dimethyl-4-iodopyridin-2-yl 568 Cl Cl CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 569 Cl Cl CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 570 Cl Cl CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 571 Cl Cl CH₂3,4,5-Trimethyl-pyridin-2-yl 572 Cl Cl CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 573 Cl Cl CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 574 Cl Cl CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 575 Cl Cl CH₂3,5-Dimethyl-4-aminopyridin-2-yl 576 Cl Br CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 577 Cl Br CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 578 Cl Br CH₂3,5-Dimethyl-4-bromopyridin-2-yl 579 Br Br CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 580 Cl Br CH₂3,5-Dimethyl-4-chloropyridin-2-yl 581 Br Br CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 582 Cl Br CH₂3,5-Dimethyl-4-iodopyridin-2-yl 583 Br Br CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 584 Cl Br CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 585 Br Br CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 586 Cl Br CH₂3,4,5-Trimethyl-pyridin-2-yl 587 Br Br CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 588 Cl Br CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 589 Cl Br CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 590 Cl Br CH₂3,5-Dimethyl-4-aminopyridin-2-yl 591 Cl I CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 592 Cl I CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 593 Cl I CH₂3,5-Dimethyl-4-bromopyridin-2-yl 594 Cl I CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 595 Cl I CH₂3,5-Dimethyl-4-chloropyridin-2-yl 596 Cl I CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 597 Cl I CH₂3,5-Dimethyl-4-iodopyridin-2-yl 598 Cl I CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 599 Cl I CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 600 Cl I CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 601 Cl I CH₂3,4,5-Trimethyl-pyridin-2-yl 602 Cl I CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 603 Cl I CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 604 Cl I CH₂4,6-Dimethyl-5-methoxy-l-oxypyridin-3-yI 605 Cl I CH₂3,5-Dimethyl-4-aminopyridin-2-yl 606 Cl CN CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 607 Cl CN CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 608 Cl CN CH₂3,5-Dimethyl-4-bromopyridin-2-yl 609 Cl CN CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 610 Cl CN CH₂3,5-Dimethyl-4-chloropyridin-2-yl 611 Cl CN CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 612 Cl CN CH₂3,5-Dimethyl-4-iodopyridin-2-yl 613 Cl CN CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 614 Cl CN CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 615 Cl CN CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 616 Cl CN CH₂3,4,5-Trimethyl-pyridin-2-yl 617 Cl CN CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 618 Cl CN CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 619 Cl CN CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 620 Cl CN CH₂3,5-Dimethyl-4-aminopyridin-2-yl 621 Cl H C(O)3,5-Dimethyl-4-methoxypyridin-2-yl 622 Cl H C(O)3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 623 Cl H C(O)3,5-Dimethyl-4-bromopyridin-2-yl 624 Cl H C(O)3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 625 Cl H C(O)3,5-Dimethyl-4-chloropyridin-2-yl 626 Cl H C(O)3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 627 Cl H C(O)3,5-Dimethyl-4-iodopyridin-2-yl 628 Cl H C(O)3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 629 Cl H C(O)3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 630 Cl H C(O)3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 631 Cl H C(O)3,4,5-Trimethyl-pyridin-2-yl 632 Cl H C(O)3,4,5-Trimethyl-1-oxypyridin-2-yl 633 Cl H C(O)4,6-Dimethyl-5-methoxypyridin-3-yl 634 Cl H C(O)4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 635 Cl H C(O)3,5-Dimethyl-4-aminopyridin-2-yl 636 Cl H S(O)3,5-Dimethyl-4-methoxypyridin-2-yl 637 Cl H S(O)3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 638 Cl H S(O)3,5-Dimethyl-4-bromopyridin-2-yl 639 Cl H S(O)3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 640 Cl H S(O)3,5-Dimethyl-4-chloropyridin-2-yl 641 Cl H S(O)3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 642 Cl H S(O)3,5-Dimethyl-4-iodopyridin-2-yl 643 Cl H S(O)3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 644 Cl H S(O)3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 645 Cl H S(O)3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 646 Cl Br S(O)3,4,5-Trimethyl-pyridin-2-yl 647 Cl H S(O)3,4,5-Trimethyl-1-oxypyridin-2-yl 648 Cl Br S(O)4,6-Dimethyl-5-methoxypyridin-3-yl 649 Cl H S(O)4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 650 Cl H SO₂3,5-Dimethyl-4-methoxypyridin-2-yl 651 Cl H SO₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 652 Cl H SO₂3,5-Dimethyl-4-bromopyridin-2-yl 653 Cl H SO₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 654 Cl Br SO₂3,5-Dimethyl-4-chloropyridin-2-yl 655 Cl H SO₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 656 Cl H SO₂3,5-Dimethyl-4-iodopyridin-2-yl 657 Cl H SO₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 658 Cl H SO₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 659 Cl H SO₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 660 Cl H SO₂3,4,5-Trimethyl-pyridin-2-yl 661 Cl H SO₂3,4,5-Trimethyl-1-oxypyridin-2-yl 662 Cl H SO₂4,6-Dimethyl-5-methoxypyridin-3-yl 663 Cl H SO₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 664 Cl i-pr C(O)3,5-Dimethyl-4-methoxypyridin-2-yI 665 Cl i-pr C(O)3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 666 Cl i-pr C(O)3,5-Dimethyl-4-bromopyridin-2-yl 667 Cl i-pr C(O)3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 668 Cl i-pr C(O)3,5-Dimethyl-4-chloropyridin-2-yl 669 Cl i-pr C(O)3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 670 Cl i-pr C(O)3,5-Dimethyl-4-iodopyridin-2-yl 671 Cl i-pr C(O)3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 672 Cl i-pr C(O)3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 673 Cl i-pr C(O)3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 674 Cl i-pr C(O)3,4,5-Trimethyl-pyridin-2-yl 675 Cl i-pr C(O)3,4,5-Trimethyl-1-oxypyridin-2-yl 676 Cl i-pr C(O)4,6-Dimethyl-5-methoxypyridin-3-yl 677 Cl i-pr C(O)4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 678 Cl i-pr C(O)3,5-Dimethyl-4-aminopyridin-2-yl 679 Cl i-pr S(O)3,5-Dimethyl-4-methoxypyridin-2-yl 680 Cl i-pr S(O)3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 681 Cl i-pr S(O)3,5-Dimethyl-4-bromopyridin-2-yl 682 Cl i-pr S(O)3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 683 Cl i-pr S(O)3,5-Dimethyl-4-chloropyridin-2-yl 684 Cl i-pr S(O)3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 685 Cl i-pr S(O)3,5-Dimethyl-4-iodopyridin-2-yl 686 Cl i-pr S(O)3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 687 Cl i-pr S(O)3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 688 Cl i-pr S(O)3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 689 Cl i-pr S(O)3,4,5-Trimethyl-pyridin-2-yl 690 Cl i-pr S(O)3,4,5-Trimethyl-1-oxypyridin-2-yl 691 Cl i-pr S(O)4,6-Dimethyl-5-methoxypyridin-3-yl 692 Cl i-pr S(O)4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 693 Cl i-pr SO₂3,5-Dimethyl-4-methoxypyridin-2-yl 694 Cl i-pr SO₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 695 Cl i-pr SO₂3,5-Dimethyl-4-bromopyridin-2-yl 696 Cl i-pr SO₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 697 Cl i-pr SO₂3,5-Dimethyl-4-chloropyridin-2-yl 698 Cl i-pr SO₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 699 Cl i-pr SO₂3,5-Dimethyl-4-iodopyridin-2-yl 700 Cl i-pr SO₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 701 Cl i-pr SO₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 702 Cl i-pr SO₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 703 Cl i-pr SO₂3,4,5-Trimethyl-pyridin-2-yl 704 Cl i-pr SO₂3,4,5-Trimethyl-1-oxypyridin-2-yl 705 Cl i-pr SO₂4,6-Dimethyl-5-methoxypyridin-3-yl 706 Cl i-pr SO₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 707 Cl H C(O)3,4,5-Trimethoxyphenyl 708 Cl H C(O) 2-Chloro-3,4,5-trimethoxyphenyl 709Cl H C(O) 2-Bromo-3,4,5-trimethoxyphenyl 710 Cl H C(O)3,5-Dimethyl-4-methoxyphenyl 711 Cl H C(O)2-Chloro-3,5-Dimethyl-4-methoxyphenyl 712 Cl H C(O)2-Bromo-3,5-Dimethyl-4-methoxyphenyl 713 Cl H SO₂ 3,4,5-Trimethoxyphenyl714 Cl H SO₂ 2-Chloro-3,4,5-trimethoxyphenyl 715 Cl H SO₂2-Bromo-3,4,5-trimethoxyphenyl 716 Cl H SO₂ 3,5-Dimethyl-4-methoxyphenyl717 Cl H SO₂ 2-Chloro-3,5-Dimethyl-4-methoxyphenyl 718 Cl H SO₂2-Bromo-3,5-Dimethyl-4-methoxyphenyl 719 Br H CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 720 Br H CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 721 Br H CH₂6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 722 Br H CH₂6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 723 Br H CH₂3,5-Dimethyl-4-bromopyridin-2-yl 724 Br H CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 725 Br H CH₂3,5-Dimethyl-4-chloropyridin-2-yl 726 Br H CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 727 Br H CH₂3,5-Dimethyl-4-iodopyridin-2-yl 728 Br H CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 729 Br H CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 730 Br H CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 731 Br H CH₂3,4,5-Trimethyl-pyridin-2-yl 732 Br H CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 733 Br H CH₂4,5,6-Trimethoxypyridin-2-yl 734 Br H CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 735 Br H CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 736 Br H CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 737 Br H CH₂3,4,5-Trimethoxy-pyridin-2-yl 738 Br H CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 739 Br H CH₂3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 740 Br H CH₂3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 741 Br H CH₂4,5,6-Trimethyl-pyridin-2-yl 742 Br H CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 743 Br H CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 744 Br H CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 745 Br H CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 746 Br H CH₂4,6-Dimethyl-5-bromopyridin-3-yl 747 Br H CH₂4,6-Dimethyl-5-chloropyridin-3-yl 748 Br H CH₂5,6-Dimethyl-4-bromopyridin-3-yl 749 Br H CH₂5,6-Dimethyl-4-chloropyridin-3-yl 750 Br H CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 751 Br H CH₂2,6-Dimethyl-pyridin-4-yl 752 Br H CH₂ 2,3,6-Trimethyl-pyridin-4-yl 753Br H CH₂ 2,3,6-Trimethoxy-pyridin-4-yl 754 Br H CH₂2,6-Dimethyl-3-bromopyridin-4-yl 755 Br H CH₂2,6-Dimethyl-3-chloropyridin-4-yl 756 Br H CH₂2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 757 Br H CH₂2,6-Dimethyl-1-oxy-pyridin-4-yl 758 Br H CH₂2,3,6-Trimethyl-1-oxy-pyridin-4-yl 759 Br H CH₂2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 760 Br H CH₂2,6-Dimethyl-3-bromol-oxy-pyridin-4-yl 761 Br H CH₂2,6-Dimethyl-3-chlorol-oxy-pyridin-4-yl 762 Br H CH₂4,6-Dimethyl-5-iodopyridin-3-yl 763 Br H CH₂3,5-Dimethyl-4-aminopyridin-2-yl 764 Br i-pr CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 765 Br i-pr CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 766 Br i-pr CH₂6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 767 Br i-pr CH₂6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 768 Br i-pr CH₂3,5-Dimethyl-4-bromopyridin-2-yl 769 Br i-pr CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 770 Br i-pr CH₂3,5-Dimethyl-4-chloropyridin-2-yl 771 Br i-pr CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 772 Br i-pr CH₂3,5-Dimethyl-4-iodopyridin-2-yl 773 Br i-pr CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 774 Br i-pr CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 775 Br i-pr CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yI 776 Br i-pr CH₂3,4,5-Trimethyl-pyridin-2-yl 777 Br i-pr CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 778 Br i-pr CH₂4,5,6-Trimethoxypyridin-2-yl 779 Br i-pr CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 780 Br i-pr CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 781 Br i-pr CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 782 Br i-pr CH₂3,4,5-Trimethoxy-pyridin-2-yl 783 Br i-pr CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 784 Br i-pr CH₂3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 785 Br i-pr CH₂3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 786 Br i-pr CH₂4,5,6-Trimethyl-pyridin-2-yl 787 Br i-pr CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 788 Br i-pr CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 789 Br i-pr CH₂ 4,6-Dimethyl-5-methoxypyridin-3 -yl 790 Br i-pr CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 791 Br i-pr CH₂4,6-Dimethyl-5-bromopyridin-3-yl 792 Br i-pr CH₂4,6-Dimethyl-5-chloropyridin-3-yl 793 Br i-pr CH₂5,6-Dimethyl-4-bromopyridin-3-yl 794 Br i-pr CH₂5,6-Dimethyl-4-chloropyridin-3-yl 795 Br i-pr CH₂ 2,6-Dimethyl-3-methoxypyridin-4-yl 796 Br i-pr CH₂ 2,6-Dimethyl-pyridin-4-yl 797 Bri-pr CH₂ 2,3,6-Trimethyl-pyridin-4-yl 798 Br i-pr CH₂2,3,6-Trimethoxy-pyridin-4-yl 799 Br i-pr CH₂2,6-Dimethyl-3-bromopyridin-4-yl 800 Br i-pr CH₂2,6-Dimethyl-3-chloropyridin-4-yl 801 Br i-pr CH₂2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 802 Br i-pr CH₂2,6-Dimethyl-1-oxy-pyridin-4-yl 803 Br i-pr CH₂2,3,6-Trimethyl-1-oxy-pyridin-4-yl 804 Br i-pr CH₂2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 805 Br i-pr CH₂2,6-Dimethyl-3-bromol-oxy-pyridin-4-yl 806 Br i-pr CH₂2,6-Dimethyl-3-chlorol-oxy-pyridin-4-yl 807 Br i-pr CH₂4,6-Dimethyl-5-iodopyridin-3-yl 808 Br i-pr CH₂3,5-Dimethyl-4-aminopyridin-2-yl 809 Br Ph CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 810 Br Ph CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 811 Br Ph CH₂3,5-Dimethyl-4-bromopyridin-2-yl 812 Br Ph CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 813 Br Ph CH₂3,5-Dimethyl-4-chloropyridin-2-yl 814 Br Ph CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 815 Br Ph CH₂3,5-Dimethyl-4-iodopyridin-2-yl 816 Br Ph CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 817 Br Ph CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 818 Br Ph CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 819 Br Ph CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 820 Br Ph CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 821 Br Ph CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 822 Br Ph CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 823 Br Et CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 824 Br Et CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 825 Br Et CH₂3,5-Dimethyl-4-bromopyridin-2-yl 826 Br Et CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 827 Br Et CH₂3,5-Dimethyl-4-chloropyridin-2-yl 828 Br Et CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 829 Br Et CH₂3,5-Dimethyl-4-iodopyridin-2-yl 830 Br Et CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 831 Br Et CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 832 Br Et CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 833 Br Et CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 834 Br Et CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 835 Br Et CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 836 Br Et CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 837 Br Me CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 838 Br Me CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 839 Br Me CH₂3,5-Dimethyl-4-bromopyridin-2-yl 840 Br Me CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 841 Br Me CH₂3,5-Dimethyl-4-chloropyridin-2-yl 842 Br Me CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 843 Br Me CH₂3,5-Dimethyl-4-iodopyridin-2-yl 844 Br Me CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 845 Br Me CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 846 Br Me CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 847 Br Me CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 848 Br Me CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 849 Br Me CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 850 Br Me CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 851 Br 2-Py CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 852 Br 2-Py CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 853 Br 2-Py CH₂3,5-Dimethyl-4-bromopyridin-2-yl 854 Br 2-Py CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 855 Br 2-Py CH₂3,5-Dimethyl-4-chloropyridin-2-yl 856 Br 2-Py CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 857 Br 2-Py CH₂3,5-Dimethyl-4-iodopyridin-2-yl 858 Br 2-Py CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 859 Br 2-Py CH₂ 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 860 Br 2-Py CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 861 Br 2-Py CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 862 Br 2-Py CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 863 Br 2-Py CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 864 Br 2-Py CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 865 Br 3-Py CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 866 Br 3-Py CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 867 Br 3-Py CH₂3,5-Dimethyl-4-bromopyridin-2-yl 868 Br 3-Py CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 869 Br 3-Py CH₂3,5-Dimethyl-4-chloropyridin-2-yl 870 Br 3-Py CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 871 Br 3-Py CH₂3,5-Dimethyl-4-iodopyridin-2-yl 872 Br 3-Py CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 873 Br 3-Py CH₂ 3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 874 Br 3-Py CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 875 Br 3-Py CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 876 Br 3-Py CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 877 Br 3-Py CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 878 Br 3-Py CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-ylCompounds of interest in Table 1 are 1, 2, 3 16, 17, 18, 27, 28, 47, 48,62, 63, 77, 78, 92, 93, 97, 98, 129, 130, 242, 243, 245, 246, 247, 248,249, 250, 251, 252, 253, 267, 268, 287, 288, 289, 290, 291, 292, 293,294, 295, 296, 297, 298, 312, 313, 332, 333, 334, 335, 336, 337, 338,339, 351, 352, 365, 366, 367, 368, 369, 370, 384, 385, 398, 399, 400,401, 417, 418, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 450,451, 464, 465, 466, 466, 467, 468, 469, 470, 471, 483, 484, 497, 498,530, 531, 550, 551, 563, 564, 575, 576, 578, 579, 590, 591, 593, 594,605, 606, 608, 609, 610, 621, 721, 722, 725, 726, 727, 728, 729, 730,746, 747, 766, 767, 791, 792, 811, 812, 823, 824, 825, 826, 839, 840,853, 854, 867, and 868, with the selected being 242, 243, 245, 246, 247,248, 267, 268, 287, 288, 312, 313, 332, 333, 334, 335, 336, 337, 338,339, 365, 369, 398, 417, 431, 432, 433, 434, 435, 436, 437, 438, 450,451, 464, 465, 483, and 484.III. Synthesis of the Compounds of the Invention

The compounds the present invention may be synthesized by variousmethods known in the art, including those described in, for example,Gillespie, WO 02/055082; Dempcy, U.S. Publication No. US 2003/0078413.For the synthesis of compounds of Formulae I and II, a general strategyis outlined in Scheme 1 and consists of three parts: (1) constructingthe bicyclic system, starting from either a pyridine or a pyrazole, (2)appending the -R⁴-R⁵ group, and (3) further elaborating the ringsystems.

Importantly, one skilled in the art will recognize that the sequence ofevents is not necessarily (1)-(2)-(3), and that these events may beinterchanged, provided there is no incompatibility between the reagentsand the functional groups specific to the point in case.

Also, the starting materials and the intermediates of the Formula 1, 2,3, or 4 can exist in tautomeric forms as shown in the followingexamples, and both forms are indiscriminately used in this patent.

1. Assembly of the pyrazolo[3.4-d]pyrimidine1.1 Assembly of the pyrazolo[3,4-d]pyrimidine Starting from a pyrimidine

The compounds of Formula 3 can be prepared from pyrimidines as outlinedin Scheme 2. For instance:

Method 1.1.1

The compound of Formula 3, wherein R⁶ is —Cl, R⁷ is —NH₂, and R³ is —H,is readily prepared by treating2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (Formula 1) withhydrazine, see, F. Seela, Heterocycles 1985, 23, 2521; F. Seela, Helv.Chim. Acta 1986, 69, 1602; and R. O. Dempcy, WO 03/022859.

Method 1.1.2

The compounds of Formula 3, wherein R⁶ is Cl, R⁷ is NH₂ and R³ is alkyl,aryl, or heteroaryl have not been previously reported. They can be madeby converting a compound of Formula I to a compound of Formula 5 in twosteps: i) Nucleophilic addition to the carbonyl group; and ii) Oxidationof the resulting alcohol. In a subsequent step, the compound of Formula5 is converted to the compound of Formula 3 by reaction with hydrazine,or an equivalent thereof.

Method 1.1.3

The compounds of Formula 3 wherein R³ is NH₂ can be obtained bytreatment of a nitrile of Formula 6 with hydrazine (See, A. M. El-Reedy,Phosphorus, Sulfur, Silicon, Relat. Elem. 1989, 42, 231).

The compounds of Formula 3 wherein R³ is OH can be obtained by treatmentof a nitrile of Formula 6 with hydrazine followed by hydrolysis (See,Ciba, Patent No. UK 884,151 (1961)).

Method 1.1.4

The compounds of Formula 3 wherein R³ is OH can be obtained by treatmentof an acid, ester, or activated ester (or equivalent thereof) of Formula7 with hydrazine (Ciba, Patent No. UK 884,151 (1961)).

1.2. Assembly of the pyrazolo[3,4-d]pyrimidine Starting from a pyrazole

The compounds of Formula 3 can also be made from pyrazoles of Formula 2(Scheme 3). There are a variety of methods by which the 6-membered ringcan be formed (e.g R. J. Bontems, J. Med Chem, 1990, 33, 2174 andreferences therein). For instance:

Compounds of Formula 2 wherein R¹³ is —CONH₂ and R¹⁴ is NH₂ can betreated with Ph—CO—NCS to give compounds of Formula 3 in which R⁶ is OHand R⁷ is NH₂ (F. Babin, J. Heterocycl. Chem. 1983, 20, 1169.)

Compounds of Formula 2 wherein R¹³ is —CN and R¹⁴ is NH₂ can be treatedwith thiourea or guanidine to give compounds of Formula 3 in which R⁶ isNH₂ and R⁷ is NH₂ (H. Kosaku, Heterocycles, 2001, 55, 2279).

Compounds of Formula 2 wherein R¹³ is —CONH₂ and R¹⁴ is NH₂ can betreated with CS₂ or EtOCS₂K to give compounds of Formula 3 in which R⁶is OH and R⁷ is SH (S. M. Bennett, J. Med. Chem. 1990, 33, 2162).

2. Incorporation of the —R⁴—R⁵ Fragment.

2.1. Alkylation of Compounds of Formula 3.

Compounds of Formula 3 can be alkylated in the presence of a base suchas K₂CO₃, NaH, Cs₂CO₃, DBU etc. with/without the presence of a catalystsuch as Nal, KI, (Bu)₃NI etc., and in a polar solvent such as DMF, THF,DMSO etc. using electrophiles such as L₁-R⁴—R⁵ where L₁ is a leavinggroup. Leaving groups include but are not limited to, e.g., halogen,triflate, tosylate, mesylate, triphenylphosphonium (generated underMitsunobu conditions, e.g PPh₃/DEAD) etc. (See Kasibhatla, WO 03/037860)

2.2. Preparation of Electrophiles L₁-R⁴—R⁵ wherein L₁ is a leaving groupand of Nucleophiles NH₂—R⁴—R⁵.

2.2.1. Synthesis of Benzyl Type Electrophiles:

The electrophiles can be prepared from the substituted benzenederivatives using various methods reported in the literature, see JerryMarch, Advanced Organic Chemistry, 4^(th) edition; Larock, ComprehensiveOrganic Transformations, 1989, VCH, New York. For example the compoundswherein L₁ is Br can be prepared by reduction of the correspondingbenzoic acid or benzaldehyde, followed by halogenation. These benzylderivatives can also be prepared by benzylic oxidation or benzylichalogenation. Further modification of the benzyl ring can be done beforeor after the pyrazolo[3,4-d]pyrimidine alkylation step. Thecorresponding amines where L₁ is NH₂ can be prepared by a variety ofmethods, for instance from compounds where L₁ is leaving group such aschloride, bromide, tosylate, mesylate etc. using ammonia, or with sodiumazide followed by hydrogenation.

2.2.2. Synthesis of Pyridyl Methyl Type Electrotphiles:

These compounds can be prepared from many methods reported in theliterature. Morisawa, J. Med. Chem. 1974, 17, 1083; Klaus, W., J. MedChem. 1992, 35, 438; Abramovitch, R. A.; Smith, E. M. “Pyridine-1-oxidein Pyridine and its Derivatives” in The Chemistry of HeterocyclicCompounds; Weissberger, A., Taylor, E. C., Eds.; John Wiley, New York,1974, Pt. 2, pp 1-261; Jeromin, G. E., Chem. Ber. 1987, 120, 649. Blanz,E. J., J. Med. Chem. 1970, 13, 1124; Smith, Kline and French, EP0184322, 1986; Abblard, J., Bull. Soc. Chim. Fr. 1972, 2466; Fisher, B.E., “The Structure of Isomaltol” J. Org. Chem. 1964, 29, 776. De Cat,A., Bull. Soc. Chim. Belg. 1965, 74, 270; Looker, J. H., J. Org. Chem.1979, 44, 3407. Ackerman, J. F. Ph.D. Dissertation, University of NotreDame, June, 1949. These methods can be applied to the synthesis ofquinoline and isoquinolines type compounds.

3. Further Elaboration of the Ring Systems.

3.1. Functional Group Interconversions of R¹:

Compounds of Formula I, wherein R¹ is —OH, can be converted to halidesusing standard conditions POCl₃, POBr₃ etc. with/without the presence ofbase such as Et₃N, N,N-dimethylaniline, (i-Pr)₂NEt etc. and with/withouta catalyst such as BnEt₃N⁺Cl⁻, in polar solvents such as CH₃CN, CH₂Cl₂etc. Related methods include, but are not limited to, SOCl₂/DMF (M. J.Robins, Can. J. Chem. 1973, 12, 3161), PPh₃/CCl₄ (L. De Napoli, J. Chem.Soc. Perkin Trans 1, 1994, 923), HMPT/CCl₄ or HMPT/NBS (E. A. Veliz,Tetrahedron Lett, 2000, 41, 1695) or PPh₃/I₂ (X. Lin, Org. Letters,2000, 2, 3497).

Compounds of Formula I, wherein R¹ is —NH₂, can be converted to halidesby a Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I) by means of anitrosylating agent (e.g NaNO₂/H⁺, NOBF₄, RONO) and a halogen donor(e.g. BF₄ ⁻, CuX₂, SbX₃, where X is a halogen).

Compounds of Formula I, wherein R¹ is alkyl can be prepared fromcompounds of Formula 3 where R¹ is halogen and trialkyl aluminum ordialkyl zinc (A. Holy, J. Med Chem. 1999, 42, 2064).

Compounds of Formula I, wherein R¹ is a halide can be converted tocompounds wherein R¹ is —NH₂, —OH, —SH, —OR, —SR with standard reagents,e.g NH₃, NaOH, thiourea, RO⁻, RS⁻, with or without a catalyst (e.g. Pd,Ni, Cu, Lewis acid, H⁺), wherein R is lower alkyl.

3.2. Functional Group Interconversions of R²:

Compounds of Formula I, wherein R² is —NH₂ can be temporarily protected,e.g as an amide (Ac₂O, PivCl, (tBoc)₂O) or a formamidine (DMF-DMA).

Compounds of Formula I, wherein R² is NH₂ can be converted to halides bya Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I) by means of anitrosylating agent (e.g. NaNO₂/H⁺, NOBF₄, RONO) and a halogen donor(e.g BF₄ ⁻, CuX₂, SbX₃) where X is a halogen.

Compounds of Formula I, wherein R² is a halide can be converted tocompounds wherein R² is NH₂, OH, SH, OR⁸, SR⁸ with standard reagents,e.g NH₃, NaOH, thiourea, R⁸O⁻, R⁸S⁻, with or without a catalyst (e.g.Pd, Ni, Cu, Lewis acid, H⁺).

Compounds of Formula I, wherein R² is SH can be converted to halides(Br₂). They can also be oxidized (e.g H₂O₂) and treated with ammonia togive a NH₂ group (S. M. Bennett, J. Med. Chem. 1990, 33, 2162).

Compounds of Formula I, wherein R² is a sulfide, e.g MeS—, can beconverted to a sulfone, e.g. MeSO₂ ⁻, and displaced with a nucleophile,e.g. NH₃ or NH₂—NH₂, N₃ ⁻, CN⁻.

3.3. Functional Group Interconversions of R³:

Compounds of Formula I, wherein R³ is H can be converted to compounds ofFormula I wherein R³ is a halogen (e.g. NCS, NBS, NIS, Br₂, ICl, I₂/KOH.F. Seela et al, Helv. Chim. Acta 1999, 82, 105).

Compounds of Formula I wherein R³ is a halogen can be functionalized byPd-catalyzed reactions ((a) Sonogashira coupling: E. C. Taylor et al,Tetrahedron, 1992, 48, 8089. (b) carboxylation: J. W. Pawlik, J.Heterocycl. Chem. 1992, 29, 1357 (c) Suzuki coupling (T. Y. I Wu, Org.Lett., 2003, 5, 3587) or by addition of nucleophiles (e.g. hydrazine, B.M. Lynch, Can. J Chem. 1988, 66, 420).

Compounds of Formula I, wherein R³ is a halide can be converted tocompounds wherein R³ is NH₂, OH, SH, OR⁸, SR⁸ with standard reagents,e.g. NH₃, NaOH, thiourea, R⁸O⁻, R⁸S⁻, with or without a catalyst (e.g.Pd, Ni, Cu, Lewis acid, H⁺).

Compounds of Formula I, wherein R³ is MeO can be demethylated to providecompounds of Formula I, wherein R³ is OH (J. D. Anderson, J. Heterocycl.Chem., 1990 27, 439).

3.4. Further Elaboration of R⁵:

R⁵ especially when it is aryl or heteroaryl, can be further modified asneeded, for example by halogenation, nitration, palladium coupling ofhalogen, Friedel-Crafts alkylation/acylation, etc. or thesemodifications can also be done before alkylation, see Jerry March,Advanced Organic Chemistry. The heteroaromatic rings can also beoxidized to their corresponding N-oxides using various oxidizing agentssuch as H₂O₂, O₃, MCPBA etc. in polar solvents such as CH₂Cl₂, CHCl₃,CF₃COOH etc. See Jerry March, Advanced Organic Chemistry, 4th edition,Chapter 19. Examples of modifications are suggested in Scheme 5.

4. Permutations of the Order of Events

As mentioned above, the events (1) assembly of the bicyclic system (2)appendage of the R⁵—R⁴— moiety, and (3) further elaboration of the ringsystems do not necessarily have to be made in the sequence of(1)-(2)-(3), and it may be beneficial to proceed in a differentsequence.

For illustrative purposes, Scheme 6 shows a putative synthesis in whichthe order of events is not (1)-(2)-(3), but is (1)-(3)-(2).

First the bicyclic system is prepared, then it is elaborated, andfinally R⁵ is appended via an alkylation.

For illustrative purposes, Scheme 7 shows a putative synthesis in whichthe order of events is not (1)-(2)-(3), but is (2)-(1)-(3). First the R⁵group is appended to a pyrimidine via an aromatic nucleophilicsubstitution, then the bicyclic ring system is constructed, and finallya series of functional group interconversions yields the compound ofFormula I.

Also, if R⁵ is, for instance, a pyridine, it can be converted to aN-oxide either before or after alkylation.

IV. Pharmaceutical Compositions, Dosing, and Modes of Administration

The present invention is directed to the clinical use of theheterocyclics, in particular, the pyrazolopyrimidines and their relatedanalogs of Formulae A, I and II, and their polymorphs, solvates, esters,tautomers, diastereomers, enantiomers, pharmaceutically acceptable saltsand prodrugs thereof, for use in treatment or prevention of diseasesthat are HSP90-dependent. For example, a disorder such as inflammatorydiseases, infections, autoimmune disorders, stroke, ischemia, cardiacdisorder, neurological disorders, fibrogenetic disorders, proliferativedisorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolicdiseases, and malignant disease. The fibrogenetic disorders include butare not limited to scleroderma, polymyositis, systemic lupus, rheumatoidarthritis, liver cirrhosis, keloid formation, interstitial nephritis andpulmonary fibrosis.

The present invention features pharmaceutical compositions comprisingthe compound of Formulae A, I and II, or a polymorph, solvate, ester,tautomer, enantiomer, diastereomer, pharmaceutically acceptable saltthereof, or prodrug thereof, of any of the preceding aspect andembodiments and one or more pharmaceutical excipients.

Those of ordinary skill in the art are familiar with formulation andadministration techniques that can be employed with the compounds andmethods of the invention, e.g., as discussed in Goodman and Gilman, ThePharmacological Basis of Therapeutics, (current edition), Pergamon; andRemington's, Pharmaceutical Sciences (current edition), Mack PublishingCo., Easton, Pa.

The compounds utilized in the methods of the instant invention may beadministered either alone or in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practices. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal andtopical routes of administration.

For example, the therapeutic or pharmaceutical compositions of theinvention can be administered locally to the area in need of treatment.This may be achieved by, for example, but not limited to, local infusionduring surgery, topical application, e.g., cream, ointment, injection,catheter, or implant, said implant made, e.g., out of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. The administration can also be by directinjection at the site (or former site) of a tumor or neoplastic orpre-neoplastic tissue.

Still further, the compounds or compositions of the invention can bedelivered in a vesicle, e.g., a liposome (see, for example, Langer,Science 1990, 249, 1527-1533; Treat et al., Liposomes in the Therapy ofInfectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss,N.Y., pp. 353-365, 1989).

The compounds and pharmaceutical compositions used in the methods of thepresent invention can also be delivered in a controlled release system.In one embodiment, a pump may be used (see, Sefton, 1987, CRC Crit. RefBiomed. Eng. 14:201; Buchwald et al. Surgery, 1980, 88, 507; Saudek etal. N. Engl. J. Med. 1989, 321, (574). Additionally, a controlledrelease system can be placed in proximity of the therapeutic target.(See, Goodson, Medical Applications of Controlled Release, 1984, 2,115-138).

The pharmaceutical compositions used in the methods of the instantinvention can also contain the active ingredient in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs. Compositions intended for oral use maybe prepared according to any method known to the art for the manufactureof pharmaceutical compositions, and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,such as microcrystalline cellulose, sodium crosscarmellose, corn starch,or alginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be un-coatedor coated by known techniques to mask the taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, or cellulose acetate butyrate may be employed as appropriate.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachisd oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The compounds and pharmaceutical compositions used in the methods of theinstant invention may also be in the form of an oil-in-water emulsions.The oily phase may be a vegetable oil, for example olive oil or arachisoil, or a mineral oil, for example liquid paraffin or mixtures of these.Suitable emulsifying agents may be naturally-occurring phosphatides, forexample soy bean lecithin, and esters or partial esters derived fromfatty acids and hexitol anhydrides, for example sorbitan monooleate, andcondensation products of the said partial esters with ethylene oxide,for example polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening agents, flavoring agents, preservatives andantioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solution. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulsion.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

The compounds of the present invention used in the methods of thepresent invention may also be administered in the form of suppositoriesfor rectal administration of the drug. These compositions can beprepared by mixing the inhibitors with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing a compound or composition of the invention can be used.As used herein, topical application can include mouth washes andgargles.

The compounds used in the methods of the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles and delivery devices, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

The methods, compounds and compositions of the instant invention mayalso be used in conjunction with other well known therapeutic agentsthat are selected for their particular usefulness against the conditionthat is being treated. For example, the instant compounds may be usefulin combination with known anti-cancer and cytotoxic agents. Further, theinstant methods and compounds may also be useful in combination withother inhibitors of parts of the signaling pathway that links cellsurface growth factor receptors to nuclear signals initiating cellularproliferation.

The methods of the present invention may also be useful with otheragents that inhibit angiogenesis and thereby inhibit the growth andinvasiveness of tumor cells, including, but not limited to VEGF receptorinhibitors, including ribozymes and antisense targeted to VEGFreceptors, angiostatin and endostatin.

Examples of antineoplastic agents that can be used in combination withthe compounds and methods of the present invention include, in general,and as appropriate, alkylating agents, anti-metabolites,epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors,procarbazines, mitoxantrones, platinum coordination complexes,biological response modifiers and growth inhibitors,hormonal/anti-hormonal therapeutic agents and haematopoietic growthfactors. Exemplary classes of antineoplastic include the anthracyclines,vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones,discodermolides, pteridines, diynenes and podophyllotoxins. Particularlyuseful members of those classes include, for example, carminomycin,daunorubicin, aminopterin, methotrexate, methopterin,dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil,6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin orpodo-phyllotoxin derivatives such as etoposide, etoposide phosphate orteniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine,leurosine, paclitaxel and the like. Other useful antineoplastic agentsinclude estramustine, carboplatin, cyclophosphamide, bleomycin,gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa,cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase,camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide,leuprolide, pyridobenzoindole derivatives, interferons and interleukins.

When a compound or composition of the invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer, for example,breast cancer. Administration typically occurs in an amount of betweenabout 0.01 mg/kg of body weight to about 100 mg/kg of body weight perday (administered in single or divided doses), more preferably at leastabout 0.1 mg/kg of body weight per day. A particular therapeutic dosagecan include, e.g., from about 0.01 mg to about 1000 mg of compound, andpreferably includes, e.g., from about 1 mg to about 1000 mg. Thequantity of active compound in a unit dose of preparation may be variedor adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to300 mg, more preferably 10 mg to 200 mg, according to the particularapplication. The amount administered will vary depending on theparticular IC₅₀ value of the compound used and the judgment of theattending clinician taking into consideration factors such as health,weight, and age. In combinational applications in which the compound isnot the sole active ingredient, it may be possible to administer lesseramounts of compound and still have therapeutic or prophylactic effect.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small amounts until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired.

The amount and frequency of administration of the compounds andcompositions of the present invention used in the methods of the presentinvention, and if applicable other chemotherapeutic agents and/orradiation therapy, will be regulated according to the judgment of theattending clinician (physician) considering such factors as age,condition and size of the patient as well as severity of the diseasebeing treated.

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents.

Also, in general, the compounds of the invention need not beadministered in the same pharmaceutical composition as achemotherapeutic agent, and may, because of different physical andchemical characteristics, be administered by a different route. Forexample, the compounds/compositions may be administered orally togenerate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

The particular choice of compound (and where appropriate,chemotherapeutic agent and/or radiation) will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol.

The compounds/compositions of the invention (and where appropriatechemotherapeutic agent and/or radiation) may be administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) or sequentially, depending upon the natureof the proliferative disease, the condition of the patient, and theactual choice of chemotherapeutic agent and/or radiation to beadministered in conjunction (i.e., within a single treatment protocol)with the compound/composition.

In combinational applications and uses, the compound/composition and thechemotherapeutic agent and/or radiation need not be administeredsimultaneously or essentially simultaneously, and the initial order ofadministration of the compound/composition, and the chemotherapeuticagent and/or radiation, may not be important. Thus, thecompounds/compositions of the invention may be administered firstfollowed by the administration of the chemotherapeutic agent and/orradiation; or the chemotherapeutic agent and/or radiation may beadministered first followed by the administration of thecompounds/compositions of the invention. This alternate administrationmay be repeated during a single treatment protocol. The determination ofthe order of administration, and the number of repetitions ofadministration of each therapeutic agent during a treatment protocol, iswell within the knowledge of the skilled physician after evaluation ofthe disease being treated and the condition of the patient. For example,the chemotherapeutic agent and/or radiation may be administered first,especially if it is a cytotoxic agent, and then the treatment continuedwith the administration of the compounds/compositions of the inventionfollowed, where determined advantageous, by the administration of thechemotherapeutic agent and/or radiation, and so on until the treatmentprotocol is complete.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of acompound/composition for treatment according to the individual patient'sneeds, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thepatient as well as more definite signs such as relief of disease-relatedsymptoms, inhibition of tumor growth, actual shrinkage of the tumor, orinhibition of metastasis. Size of the tumor can be measured by standardmethods such as radiological studies, e.g., CAT or MRI scan, andsuccessive measurements can be used to judge whether or not growth ofthe tumor has been retarded or even reversed. Relief of disease-relatedsymptoms such as pain, and improvement in overall condition can also beused to help judge effectiveness of treatment.

V. Assays for Determining HSP90 Binding and Downstream Effect

A variety of in vitro and in vivo assays are available to test theeffect of the compounds of the invention on HSP90. HSP90 competitivebinding assays and functional assays can be performed as known in theart substituting in the compounds of the invention. Chiosis et al.Chemistry & Biology 2001, 8, 289-299, describe some of the known ways inwhich this can be done. For example, competition binding assays using,e.g., geldanamycin or 17-AAG as a competitive binding inhibitor of HSP90can be used to determine relative HSP90 affinity of the compounds of theinvention by immobilizing the compound of interest or other competitiveinhibitor on a gel or solid matrix, preincubating HSP90 with the otherinhibitor, passing the preincubated mix over the gel or matrix, and thenmeasuring the amount of HSP90 that retains or does not retain on the gelor matrix.

Downstream effects can also be evaluated based on the known effect ofHSP90 inhibition on function and stability of various steroid receptorsand signaling proteins including, e.g., Raf1 and HER2. Compounds of thepresent invention induce dose-dependent degradation of these molecules,which can be measured using standard techniques. Inhibition of HSP90also results in up-regulation of HSP90 and related chaperone proteinsthat can similarly be measured. Antiproliferative activity on variouscancer cell lines can also be measured, as can morphological andfunctional differentiation related to HSP90 inhibition.

Many different types of methods are known in the art for determiningprotein concentrations and measuring or predicting the level of proteinswithin cells and in fluid samples. Indirect techniques include nucleicacid hybridization and amplification using, e.g., polymerase chainreaction (PCR). These techniques are known to the person of skill andare discussed, e.g., in Sambrook, Fritsch & Maniatis Molecular Cloning:A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold SpringHarbor, N.Y., 1989; Ausubel, et al. Current Protocols in MolecularBiology, John Wiley & Sons, N.Y., 1994, and, as specifically applied tothe quantification, detection, and relative activity of HER2/Neu inpatient samples, e.g., in U.S. Pat. Nos. 4,699,877, 4,918,162,4,968,603, and 5,846,749. A brief discussion of two generic techniquesthat can be used follows.

The determination of whether cells overexpress or contain elevatedlevels of HER2 can be determined using well known antibody techniquessuch as immunoblotting, radioimmunoassays, western blotting,immunoprecipitation, enzyme-linked immunosorbant assays (ELISA), andderivative techniques that make use of antibodies directed against HER2.As an example, HER2 expression in breast cancer cells can be determinedwith the use of an immunohistochemical assay, such as the Dako Hercep™test (Dako Corp., Carpinteria, Calif.). The Hercep™ test is an antibodystaining assay designed to detect HER2 overexpression in tumor tissuespecimens. This particular assay grades HER2 expression into fourlevels: 0, 1, 2, and 3, with level 3 representing the highest level ofHER2 expression. Accurate quantitation can be enhanced by employing anAutomated Cellular Imaging System (ACIS) as described, e.g., by Press,M. et al. Modern Pathology 2000, 13, 225A.

Antibodies, polyclonal or monoclonal, can be purchased from a variety ofcommercial suppliers, or may be manufactured using well-known methods,e.g., as described in Harlow et al. Antibodies: A Laboratory Manual, 2nded; Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1988.

HER2 overexpression can also be determined at the nucleic acid levelsince there is a reported high correlation between overexpression of theHER2 protein and amplification of the gene that codes for it. One way totest this is by using RT-PCR. The genomic and cDNA sequences for HER2are known. Specific DNA primers can be generated using standard,well-known techniques, and can then be used to amplify template alreadypresent in the cell. An example of this is described in Kurokawa, H. etal. Cancer Res. 2000, 60, 5887-5894. PCR can be standardized such thatquantitative differences are observed as between normal and abnormalcells, e.g., cancerous and noncancerous cells. Well known methodsemploying, e.g., densitometry, can be used to quantitate and/or comparenucleic acid levels amplified using PCR.

Similarly, fluorescent in situ hybridization (FISH) assays and otherassays can be used, e.g., Northern and/or Southern blotting. These relyon nucleic acid hybridization between the HER2 gene or mRNA and acorresponding nucleic acid probe that can be designed in the same or asimilar way as for PCR primers, above. See, e.g., Mitchell M S, andPress M. F. Oncol., Suppl. 1999, 12, 108-116. For FISH, this nucleicacid probe can be conjugated to a fluorescent molecule, e.g.,fluorescein and/or rhodamine, that preferably does not interfere withhybridization, and which fluorescence can later be measured followinghybridization. See, e.g., Kurokawa, H et al, Cancer Res. 2000, 60,5887-5894 (describing a specific nucleic acid probe having sequence5′-FAM-NucleicAcid-TAMRA-p-3′ sequence). ACIS-based approaches asdescribed above can be employed to make the assay more quantitative (dela Torre-Bueno, J., et al. Modern Pathology 2000, 13, 221A).

Immuno and nucleic acid detection can also be directed against proteinsother than HSP90 and HER2, which proteins are nevertheless affected inresponse to HSP90 inhibition.

The following examples are offered by way of illustration only and arenot intended to be limiting of the full scope and spirit of theinvention.

EXAMPLES

I. Materials and Methods

The chemical reagents used to create the novel products of the inventionbelow are all available commercially, e.g., from Aldrich Chemical Co.,Milwaukee, Wis., USA. Otherwise their preparation is facile and known toone of ordinary skill in the art, or it is referenced or describedherein.

The final compounds were usually purified by preparative TLC (silica gel60 Å, Whatman Partisil PK6F) or flash chromatography (silica gel 60 Å,EMD Chemicals) using EtOAc/hexane or MeOH/CH₂Cl₂ as eluents. Rf's weremeasured using silica gel TLC plates (silica gel 60 Å, EMD Chemicals).Analytical HPLC chromatograms were obtained using a C18 column (AgilentZorbax 300SB-C18; 5 microns; 4.6 mm×150 mm). A gradient was appliedbetween solvent A (0.1% TFA in H₂O) and solvent B (0.5% TFA in CH₃CN)increasing the proportion of A linearly from 5% (t=0) to 100% (t=7.00min), with a constant flow rate of 1 mL/min. The samples were diluted totypically 0.1-1 mg/mL in MeOH or CH₃CN and the injection volumes weretypically 10 μL. The column was not heated, and UV detection waseffected at 254 nm. ¹H-NMR spectra were recorded on a Bruker Avance 400MHz spectrometer.

The chemical names were generated using the Beilstein Autonom 2.1software.

II. General Procedures

1. General Procedures to Prepare and Manipulate thepyrazolo[3,4-d]pyrimidine Ring

General Procedure 1.1: Alkylation of pyrazolo[3,4-d]pyrimidines at N−1

4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine was prepared as describedin Seela, F.; Stecker, H. Helv. Chim. Acta 1986, 69, 1602-1613. Asuspension of the 4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (1mmol), benzyl halide (1 mmol) and K₂CO₃ (1-3 mmol) dry DMF (5 mL) wasstirred at 22-70° C. for 0.5-16 h. Work-up (EtOAc) and purification bypreparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH₂Cl₂)yielded the pure N−1 alkylated product.

General Procedure 1.2: Preparation of 3-alkyl pyrazolo[3,4-d]pyrimidines

Step 1: 1-(2-Amino-4, 6-dichloro-pyrimidin-5-yl)-ethanol

A fine suspension of 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (3.0g, 15 mmol); (Seela, F.; Stecker, H. Helv. Chim. Acta 1986, 69, 1602) inTHF was cooled to −78° C. A 3M solution of MeMgBr in THF (25 mL, 75mmol, 5 equiv.) was added over 3 h, keeping the internal temperature at−78° C. The mixture was stirred for a further 0.5 h, quenched with 100ml H₂O, and neutralized with aw. HCl. Extraction (EtOAc) gave1-(2-amino-4,6-dichloro-pyrimidin-5-yl)-ethanol as a pale yellow solid(2.5 g, 76%) which was used without further purification.

Step 2: 1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone

1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanol (2.0 g, 9.6 mmol) wastreated with MnO₂ (20 g, 229 mmol, 24 equiv.) in 1,2-dichloroethane for16 h at 70° C. Filtration over celite and concentration gave1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone as a pale orange solid(1.4 g, 6.7 mmol, 71%), which was used without further purification.

Step 3: 4-Chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone (200 mg, 0.97 mmol) wasdissolved in CH₂Cl₂ and treated with anhydrous hydrazine (31 mg, 0.97mmol, 1 equiv.) at r.t. overnight. The precipitate was collected byfiltration, washed with CH₂Cl₂, dissolved in DMSO (0.5 mL), andpartitioned between EtOAc (100 mL) and water (25 mL). The organic layerwas dried (brine, Na₂SO₄) and concentrated to afford the title compoundas a white solid (95 mg, 0.52 mmol, 53%).

2. General Procedures to Manipulate the pyridine Ring

General Procedure 2.1: Preparation of pyridine N-oxides

A solution of the pyridine derivative (1.0 mmol) in dichloromethane orchloroform (5 mL) was cooled by means of an ice-bath, treated withm-CPBA (1.1 to 3 mmol) in three portions, and allowed to warm to r.t.The mixture was extracted with dichloromethane and washed with aqueousNaOH, followed by water. Drying (Na₂SO₄) and concentration afforded thepyridine N-oxide.

General Procedure 2.2: Preparation of 2-(acetoxvmethyl)-pyridines

A solution of the 2-methyl pyridine N-oxide (1.0 mmol) in aceticanhydride (5 mL) was heated to reflux for 0.5 h. Work-up (EtOAc), drying(MgSO₄), evaporation and purification by preparative TLC or flashchromatography afforded the 2-(acetoxymethyl) pyridine.

General Procedure 2.3: Preparation of 2-(hydroxymethyl)-pyridines

A suspension of 2-acetoxymethyl-pyridine derivative and solid K₂CO₃ inmethanol was heated to 50° C. for 5-30 min. Evaporation, work-up(EtOAc), and drying (MgSO₄) afforded the 2-hydroxymethyl pyridine.

General Procedure 2.4: Preparation of 2-(bromomethyl)-pyridines

A solution of 2-(hydroxymethyl)-pyridine (1.0 mmol) and triphenylphosphine (1.2 mmol) in dichloromethane or chloroform (5 mL) was cooledto 0° C. A solution of CBr₄ (1.5 mmol) in dichloromethane or chloroformwas added dropwise, and the resulting mixture was stirred at 0° C for0.5-1 h. Work-up followed and purification by flash chromatographyafforded the 2-(bromomethyl)-pyridine.

General Procedure 2.5: Preparation of 2-chloropyridines

A suspension of 2-(hydroxymethyl)-pyridine (10 g) in POCl₃ (30 mL) wasstirred at 110° C. for 1.5 h. The resulting viscous oil was cooled tor.t. and poured onto ice water (500 g). The pH was adjusted to 10 withsolid KOH. Work-up (CHCl₃), drying (MgSO₄) and evaporation gave the2-(chloromethyl)-pyridine, usually as a purple oil or solid, which wasused without purification.

General Procedure 2.6: Preparation of pyridinium Salts

A solution of pyridine was heated in MeOH until it dissolved. Amethanolic solution of acid (1.0 equiv of e.g HCl, MeOH) was added, andthe solvent was evaporated to give the pyridinium salt.

3. General Procedure to Manipulate benzene Rings

General Procedure 3.1: Halogenation of benzene Rings.

Variant 1: A solution of the aromatic compound in MeOH/THF/acetatebuffer (1N in each AcOH and AcONa) was treated with Br₂ (1.3 equiv) atr.t. for 5 min. The excess bromine and solvent were removed on a rotaryevaporator. Work-up (CHCl₃) and flash chromatography afforded thedesired bromobenzene.

Variant 2: A solution of the aromatic compound (7 mmol) andn-halosuccinimide (NCS, NBS, or NIS, 1.06 equiv) in acetic acid (40 mL)was heated to 40-90° C. for 0.3-1 h. Evaporation, work-up (EtOAc) andflash chromatography afforded the desired halogenated benzene.

III. Preparation of Intermediates

Example 1 2-Chloro-1-chloromethyl-3,4,5-trimethoxy-benzene

The title compound was obtained by chlorination of5-chloromethyl-1,2,3-trimethoxy-benzene with NCS according to thegeneral procedure 3.1. ¹H-NMR (CDCl₃): δ 6.82 (s, 1H), 4.70 (s, 1H),3.93 (s, 3H), 3.90 (s, 3H) 3.87 (s, 3H).

Example 2 2-Chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine

Step 1: 2-Chloromethyl-4-methoxy-3,5-dimethylpyridine-]-oxide

The title compound was obtained by oxidation of2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the generalprocedure 2.1. R.t.: 4.46 min. ¹H-NMR (CDCl₃): δ 8.05 (s, 1H), 4.93 (s,2H), 3.77 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H).

Step 2: 2-Chloro-6-chloromethyl-4-methoxy-3,5-dimethylpyridine

The title compound was obtained by treating2-chloromethyl-4-methoxy-3,5-dimethylpyridine-1-oxide with POCl₃according to the general procedure 2.5. R.t.: 6.757 min. ¹H-NMR (CDCl₃):δ 4.64 (s, 2H), 3.79 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H).

Example 3 4-Chloro-2-chloromethyl-3,5-dimethyl-pyridine

The title compound was obtained by treating2-chloromethyl-3,5-dimethyl-pyridin-4-ol (Tarbit, et al. WO 99/10326)with POCl₃ according in the same manner as the general procedure 2.5(74% yield). R.t.: 5.54 min. ¹H-NMR (CDCl₃): 8.24 (s, 1H), 4.71 (s, 2H),2.48 (s, 3H), 2.36 (s, 3H).

Example 4 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine

4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine was prepared by any of thefollowing three methods:

Method 1

Step 1: 2,3,5-Collidine-N-oxide

2,3,5-Collidine-N-oxide was obtained by oxidation of 2,3,5-collidineaccording to the general procedure 2.1 in 70% yield. R.t.: 3.96 min.¹H-NMR (CDCl₃): δ 8.03 (s, 1H), 6.90 (s, 1H), 2.47 (s, 3H), 2.31 (s,3H), 2.24 (s, 3H). m/z (%) 138.2 (M+1, 100%). Rf(20% MeOH/EtOAc): 0.35.

Step 2: 4-Bromo-2,3,5-collidine-N-oxide

2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K₂CO₃ (2.9 g, 20 mmol) weresuspended in 10 mL of CCl₄. Bromine (1 mL, 20 mmol) was added dropwise,and the reaction mixture was heated to reflux for 2 h. Work-up (EtOAc)and flash chromatography (10% MeOH/EtOAc) afforded the title compound asa solid (1.05 g, 51% yield). R.t.: 5.24 min. ¹H-NMR (CDCl₃): δ 8.06 (s,1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H). m/z (%) 216.2 (M+1,100%), 218.2 (M+3, 100%). Rf (20% MeOH/EtOAc): 0.45.

Step 3: Acetic Acid 4-bromo-3,5-dimethyl-pyridin-2-yl methyl ester

4-Bromo-2,3,5-collidine-N-oxide (0.25g, 11 mmol) was dissolved in aceticanhydride (5 mL) and the solution was heated to reflux for 30 min.Work-up and flash chromatography (50% Hexane/EtOAc) afforded the titlecompound (0.27 g, 96% yield). Rf (50% Hexane/EtOAc): 0.70. R.t.: 4.76min. ¹H-NMR (CDCl₃): δ 8.26 (s, 1H), 5.27 (s, 2H), 2.46 (s, 3H), 2.41(s, 3H).

Step 4: 4-Bromo-3, 5-dimethyl-pyridin-2-yl methanol

A suspension of acetic acid 4-bromo-3,5-dimethyl-pyridin-2-yl methylester (0.26 g, 1.0 mmol) and K₂CO₃ (excess) in MeOH (5 mL) was heated to50° C. for 15 min. Work-up (CHCl₃), evaporation, and filtration througha silica gel pad (eluent: 100% EtOAc) gave the title compound as a whitesolid (0.19 g, 88% yield). Rf (50% Hexane/EtOAc): 0.5. R.t.: 3.80 min.¹H-NMR (CDCl₃): δ 8.23 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H), 2.30 (s,3H).

Step 5: 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine

The title compound was obtained from 4-bromo-3,5-dimethyl-pyridin-2-ylmethanol according to the general procedure 2.4. R.t.: 6.32 min. ¹H-NMR(CDCl₃): δ 8.22 (s, 1H), 4.63 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H).

Method 2:

Step 1: 2-chloromethyl-3,5-dimethyl-pyridin-4-ol

The title compound was obtained by heating2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride in tolueneas described by Tarbit, et al. WO 99/10326.

Step 2: 4-bromo-2-chloromethyl-3,5-dimethyl pyridine

A mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (8.2 g, 47.8 mmol)and POBr₃ (60 g, 209 mmol) was stirred at 130° C. for 3 h. The resultingviscous oil was cooled to r.t. and poured onto ice water. The pH wasadjusted to 10 with solid KOH. Work-up (CHCl₃), drying (MgSO₄) andevaporation afforded the title compound as a purple solid (8.7 g, 78%yield) which was used without purification. R.t.: 6.03 min. ¹H-NMR(CDCl₃): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H), 2.38 (s, 3H).

Method 3:

4-bromo-2-chloromethyl-3,5-dimethyl pyridine

A suspension of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (3.24 g,14.6 mmol) in PBr₃ (8.0 ml, 85.1 mmol, 5.8 equiv.) was heated to 80° C.under nitrogen. A catalytic amount of DMF (0.50 ml, 6.4 mmol, 0.44equiv.) was added, whereupon the suspension rapidly turned into anorange solution. After 40 min., the reaction was still incomplete asjudged by HPLC. The temperature was raised to 110° C. and the reactionwas prolonged for 30 min, at which point it was complete. The mixturewas poured over ice, made basic with conc. aq. NH₄OH and extracted intoEtOAc. Washing with water, drying (brine, MgSO₄) and concentration gavethe title compound as a pink solid (1.51 g, 44%) containing 10% of animpurity by ¹H-NMR. The crude was used without further purification.¹H-NMR (CDCl₃) δ 8.19 (s, 1H), 4.59 (s, 2H), 2.48 (s, 3H), 2.37 (s, 3H).

IV. Preparation of Final Compounds

Example 54-Chloro-1-(3,4,5-trimethoxy-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (See F. Seela,Heterocycles 1985, 23, 2521; F. Seela, Helv. Chim. Acta 1986, 69, 1602;R. O. Dempcy, WO 03/022859) with 5-chloromethyl-1,2,3-trimethoxy-benzeneaccording to the general procedure 1.1. R.t. 5.68 min. ¹H-NMR (CDCl₃) δ7.93 (s, 1H), 6.59 (s, 2H), 5.37 (br. s., 4H), 3.84 (s, 6H), 3.82 (s,3H).

Example 64-Chloro-1-(2-chloro-3,4,5-trimethoxy-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with2-chloro-1-chloromethyl-3,4,5-trimethoxy-benzene according to thegeneral procedure 1.1. R.t. 6.44 min. ¹H-NMR (CDCl₃) δ 7.95 (s, 1H),6.36 (s, 1H), 5.51 (s, 2H), 5.24 (br. s, 2H), 3.90 (s, 3H), 3.86 (s,3H), 3.70 (s, 3H).

Example 74-Chloro-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (1.76 g),2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride (3.70 g),K₂CO₃ (5.17 g), and DMF (20 ml) was heated to 80° C. for 30 min, dilutedwith EtOAc, washed with water and brine, concentrated, and purified byflash chromatography to give the title compound as a white solid (0.57g). R.t. 4.46 min. ¹H-NMR (CDCl₃) δ 8.10 (s, 1H), 7.89 (s, 1H), 5.53(2H), 5.24 (br. s, 2H), 3.74 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).

Example 84-Chloro-1-(6-chloro-4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (124 mg),Cs₂CO₃ (392 mg) and crude2-chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (200 mg) in DMF(2 ml) was heated to 80° C. for 1 h, diluted with EtOAc and washed withwater. Concentration and purification by preparative TLC (EtOAc) gavethe title compound. R.t. 6.43 min. ¹H-NMR (CDCl₃) δ 7.86 (s, 1H), 5.48(s, 2H), 5.37 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H).

Example 94-Chloro-1-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (158 mg),crude 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine (204 mg), Cs₂CO₃(660 mg) and DMF was heated to 80° C. for 1.5 h, diluted with EtOAc andwashed with water. The crude material was concentrated and suspended inMeOH/DCM. Filtration gave a 2:1 mixture of regioisomers which wasfurther purified by preparative silica gel plate (EtOAc 100%). The major(less polar) isomer corresponded to the title compound. R.t. 5.45 min.¹H-NMR (CDCl₃) δ 8.22 (s, 1H), 7.90 (s, 1H), 5.57 (s, 2H), 5.28 (s, 2H),2.43 (s, 3H), 2.31 (s, 3H).

Example 104-Chloro-1-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

A solution of4-chloro-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine(50 mg) in CH₂Cl₂ (2 ml) was treated with m-CPBA (90 mg) for 10 min,diluted with CH₂Cl₂, washed with sat. aq. NaHCO₃,concentrated andre-crystallized from CHCl₃/MeOH to give the title compound as a whitesolid. R.t. 4.87 min. ¹H-NMR (DMSO-d₆) δ 8.06 (s, 1H), 7.89 (s, 1H),7.36 (s, 2H), 5.55 (s, 2H), 3.72 (s, 3H), 2.30 (s, 3H), 2.18 (s, 3H).

Example 114-Chloro-1-(3,4-dichloro-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-bromomethyl-1,2-dichloro-benzene according to general procedure 1.1.R.t. 6.89 min. ¹H-NMR (CDCl₃) δ 7.90 (s, 1H), 7.39-7.37 (m, 2H), 7.26(dd, 1H), 5.37 (s, 2H), 5.20 (br. s, 2H).

Example 124-Chloro-1-(2,5-dimethoxy-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with 2-chloromethyl-1,4-dimethoxy-benzene according to general procedure 1.1. R.t. 6.06 min.¹H-NMR (CDCl₃) δ 7.94 (s, 1H), 6.85 (d, 1H), 6.75 (dd, 1H), 6.42 (dd,1H), 5.48 (s, 2H), 5.24 (s, 2H), 3.82 (s, 3H), 3.70 (s, 3H).

Example 134-Chloro-1-(4,5-dimethoxy-2-nitro-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with1-bromomethyl-4,5-dimethoxy-2-nitro-benzene according togeneralprocedure 1.1. R.t. 5.99 min. 1H-NMR (DMSO-d₆) δ 8.06 (s, 1H), 7.71 (s,1H), 7.38 (br. s, 2H), 6.57 (s, 1H), 5.71 (s, 2H), 3.86 (s, 3H), 3.68(s, 3H).

Example 141-(4-Bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 5.64 min. ¹H-NMR (CDCl₃) δ 8.20 (s, 1H), 7.92 (s,1H), 5.61 (s, 2H), 5.21 (br. s, 2H), 2.50 (s, 3H), 2.37 (s, 3H).

Example 151-(4-Bromo-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by oxidation of1-(4-bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylaminewith m-CPBA according to general procedure 2.1. R.t. 5.57 min. ¹H-NMR(CDCl₃) δ 8.23 (s, 1H), 7.90 (s, 1H), 7.38 (s, 2H), 5.64 (s, 2H), 2.50(s, 3H), 2.30 (s, 3H).

Example 164-Chloro-1-(2,3,6-trifluoro-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with2-bromomethyl-1,3,4-trifluoro-benzene according to general procedure1.1. R.t. 7.12 min. ¹H-NMR (CDCl₃) δ 7.89(s, 1H), 7.25-7.05 (m, 1H),6.95-6.85 (m, 1H), 5.53 (s, 2H), 5.49 (br. s, 2H).

Example 17 1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanol

The title compound was obtained by treatment of2-Amino-4-chloro-pyrimidine-5-carbaldehyde with MeMgBr according togeneral procedure 1.2. R.t. 4.19 min. ¹H-NMR (DMSO-d₆) δ 7.38 (s, 1H),5.18 (bs, 2H), 5.15 (m, 1H), 3.56 (d, 3H).

Example 18 1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone

The title compound was obtained by treatment of1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanol with MnO₂ according togeneral procedure 1.2. R.t. 5.23 min. ¹H-NMR (DMSO-d₆) δ 7.90 (s, 2H),2.52 (s, 3H).

Example 19 4-Chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by treatment of1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone with hydrazineaccording to general procedure 1.2. R.t. 4.61 min. ¹H-NMR (DMSO-d₆) δ11.82 (s, 1H), 8.16 (bs, 2H), 2.46 (s, 3H).

Example 20 4-Chloro-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by treating2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde by sequentially withEtMgCl, MnO2, and hydrazine according to general procedure 1.2. R.t.4.55 min. ¹H-NMR (DMSO-d₆) δ 12.84 (s, 1H), 7.07 (s, 2H), 2.85 (m, 2H),1.27-1.23 (m, 3H).

Example 21 4-Chloro-3-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by treating2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde sequentially withi-PrMgCl, MnO₂ and hydrazine according to general procedure 1.2. R.t.6.10 min. ¹H-NMR (DMSO-d₆) δ 12.86 (s, 1H), 7.06 (s, 2H), 1.29 (d, 6H).

Example 22 4-Chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by treating2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde sequentially with PhMgCl,MnO₂ and hydrazine according to general procedure 1.2. R.t. 6.04 min.¹H-NMR (DMSO-d₆) δ 13.04 (s, 1H), 7.70 (m, 2H), 7.46 (m, 3H), 7.19 (bs,2H).

Example 234-Chloro-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 6.72 min. ¹H-NMR (CDCl₃) δ 8.20 (s, 1H), 5.47 (s,2H), 5.26 (s, 2H), 3.76 (s, 2H), 2.58 (s, 3H), 2.30 (s, 3H), 2.23 (s,3H).

Example 241-(4-Bromo-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-bromo-2-chloromethyl-3,5 -dimethyl-pyridine 1-oxide according togeneral procedure 1.1. R.t. 5.90 min. ¹H-NMR (DMSO-d₆) δ 8.25 (s, 1H),7.29 (s, 2H), 5.53 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H).

Example 254-Chloro-1-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according togeneral procedure 1.1. R.t. 5.90 min. ¹H-NMR (DMSO-d₆) δ 8.25 (s, 1H),7.30 (s, 2H), 5.54 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H).

Example 264-Chloro-1-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 5.63 min. ¹H-NMR (CDCl₃) δ 8.23 (s, 1H), 5.51 (s,2H), 5.28 (br.s 2H), 2.57 (s, 3H), 2.45 (s, 3H), 2.33 (s, 3H).

Example 274-Chloro-3-methyl-1-(3,4,5-trimethoxy-benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with5-chloromethyl-1,2,3-trimethoxy-benzene according to general procedure1.1. R.t. 6.72 min. ¹H-NMR (DMSO-d₆) δ 7.30 (s, 2H), 6.57 (s, 2H), 5.22(s, 2H), 3.71 (s, 6H), 3.62 (s, 3H), 2.47(s, 3H), 2.29 (s, 3H).

Example 281-(4-Bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 5.90 min. ¹H-NMR (DMSO-d₆) δ 8.15 (s, 1H), 7.22 (s,1H), 5.46 (s, 2H), 2.42 (s, 6H), 2.30 (s, 3H).

Example 294-Chloro-3-ethyl-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 6.02 min. ¹H-NMR (DMSO) δ 8.04 (s, 1H), 7.19 (br. s,2H), 5.39 (s, 2H), 3.71(s, 3H), 2.87-2.81 (m, 2H), 2.22 (s, 3H), 2.16(s, 3H), 1.21(m, 3H).

Example 304-Chloro-1-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 6.90 min. ¹H-NMR (DMSO-d₆) δ 8.18 (s 1H), 7.21 (s,1H), 5.47 (s, 2H), 2.87-2.81 (m, 2H), 2.39 (s, 3H), 2.27 (s, 3H), 1.21(m, 3H).

Example 314-Chloro-3-isopropyl-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-isopropyl-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylaminewith 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to thegeneral procedure 1.1. R.t. 5.75 min. ¹H-NMR (DMSO-d₆) δ 8.02 (s, 1H),7.17 (br. s, 1H), 5.40 (s, 2H), 3.71 (s, 3H), 2.23 (s, 3H), 2.16 (s,3H), 1.26 (d, 6H).

Example 324-Chloro-1-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 5.89 min. ¹H-NMR (DMSO-d₆) δ 8.06 (s, 1H), 7.68-7.66(m, 2H), 7.47-7.45 (m, 3H), 7.32 (br.s, 2H), 5.52 (s, 2H), 3.72 (s, 3H),2.27 (s, 3H), 2.16 (s, 3H).

Example 334-Chloro-1-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 6.80 min. ¹H-NMR (DMSO-d₆) δ 8.20 (s, 1H), 7.67-7.65(m, 2H), 7.47-7.45 (m, 3H), 7.34 (br.s, 2H), 5.61 (s, 2H), 2.43 (s, 3H),2.27 (s, 3H).

Example 341-(4-Bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to generalprocedure 1.1. R.t. 7.41 min. ¹H-NMR (DMSO-d₆) δ 8.15 (s, 1H), 7.67 (m,2H), 7.46 (m, 3H), 7.34 (br. s, 2H), 5.62 (s, 2H), 2.4 (s, 3H), 2.3 (s,3H).

Example 354-Chloro-1-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine

The title compound was obtained by alkylation of4-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according togeneral procedure 1.1. R.t. 7.50 min. ¹H-NMR (DMSO-d₆) δ 8.25 (s, 1H),7.57 (s, 2H), 7.42 (m, 5H), 5.67 (s, 2H), 2.49 (s, 3H), 2.26 (s, 3H).

Biology Examples Example A rHSP90 Competitive Binding Assay

Five microgram of purified rHSP90 protein (Stressgen, BC, Canada,#SPP-770) in phosphated buffered saline (PBS) was coated on 96 wellplates by incubating overnight at 4° C. Unbound protein was removed andthe coated wells were washed twice with 200 μL PBS. DMSO controls(considered as untreated samples) or test compounds were then added at100-30-10-3-1-0.3 μM dilutions (in PBS), the plates mixed for 30 secondson the plate shaker, and then incubated for 60 min. at 37° C. The wellswere washed twice with 200 μL PBS, and 10 μM biotinylated-geldanamycin(biotin-GM) was added and incubated for 60 min. at 37° C. The wells werewashed again twice with 200 μL PBS, before the addition of 20 μg/mLstreptavidin-phycoerythrin (streptavidin-PE) (Molecular Probes, Eugene,Oreg.) and incubation for 60 min. at 37° C. The wells were washed againtwice with 200 μL PBS. Relative fluorescence units (RFU) was measuredusing a SpectraMax Gemini XS Spectrofluorometer (Molecular Devices,Sunnyvale, Calif.) with an excitation at 485 nm and emission at 580 nm;data was acquired using SOFTmaxPRO software (Molecular DevicesCorporation, Sunnyvale, Calif.). The background was defined as the RFUgenerated from wells that were not coated with HSP90 but were treatedwith the biotin-GM and streptavidin-PE. The background measurements weresubstrated from each sample treated with biotin-GM and streptavidin-PEmeasurements before other computation. Percent inhibition of binding foreach sample was calculated from the background subtracted values asfollows:% binding inhibition=[RFU untreated−RFU treated]/RFU untreated]×100.

Example B Cell Lysate Binding Assay

MCF7 breast carcinoma cell lysates were prepared by douncing in lysingbuffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl₂, 100 mM KCl), andthen incubated with or without test compound for 30 mins at 4° C.,followed by incubation with biotin-GM linked to BioMag™ streptavidinmagnetic beads (Qiagen) for 1 hr at 4° C. The tubes were placed on amagnetic rack, and the unbound supernatant removed. The magnetic beadswere washed three times in lysis buffer and boiled for 5 mins at 95° C.in SDS-PAGE sample buffer. Samples were analyzed on SDS protein gels,and Western blots done for rHSP90. Bands in the Western Blots werequantitated using the Bio-rad Fluor-S MultiImager, and the % inhibitionof binding of rHSP90 to the biotin-GM was calculated.

The lysate binding ability of selected compounds of the invention basedon the above assay is summarized in Table 2. The IC₅₀ reported is theconcentration of test compound needed to achieve 50% inhibition of thebiotin-GM binding to rHSP90 in the MCF7 cell lysates.

Example C HER2 Degradation Assay

MCF7 breast carcinoma cells (ATCC) were grown in Dulbecco's modifiedEagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and 10 mMHEPES, and plated in 24 well plates (50% confluent). Twenty-four hrslater (cells are 65-70% confluent), test compounds were added andincubated overnight for 16 h. For the less potent compounds, the amountsadded were 100 μM, 30 μM, 10 μM and 1 μM, and for more potent compounds,the amounts added were 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM and 0.003μM. The wells were washed with 1 mL phosphate buffered saline (PBS), and200 μL trypsin was added to each well. After trypsinization wascomplete, 50 μL of FBS was added to each well. Then 200 μL cells wastransferred to 96 well plates. The cells were pipetted up and down toobtain a single cell suspension. The plates were centrifuged at 2,500rpm for 1 min using a Sorvall Legend RT™ tabletop centrifuge (KendroLaboratory Products, Asheville, N.C.). The cells were then washed oncein PBS containing 0.2% BSA and 0.2% sodium azide (BA buffer).Phycoerythrin (PE) conjugated anti HER2/Neu antibody (Becton Dickinson,#340552), or PE conjugated anti-keyhole limpet hemacyanin [KLH] (BectonDickinson, #340761) control antibody was added at a dilution of 1:20 and1:40 respectively (final concentration was 1 μg/mL) and the cells werepipeted up and down to form a single cell suspension, and incubated for15 mins. The cells were washed twice with 200 μL BA buffer, andresuspended in 200 μL BA buffer, and transferred to FACSCAN tubes withan additional 250 μL BA buffer. Samples were analyzed using aFACSCalibur™ flow cytometer (Becton Dickinson, San Jose, Calif.)equipped with Argon-ion laser that emits 15 mW of 488 nm light forexcitation of the PE fluorochrome. 10,000 events were collected persample. A fluorescence histogram was generated and the mean fluorescenceintensity (MFI) of each sample was determined using Cellquest software.The background was defined as the MFI generated from cells incubatedwith control IgG-PE, and was subtracted from each sample stained withthe HER2/Neu antibody. Cells incubated with DMSO was always done asuntreated controls since the compounds were resuspended in DMSO. Percentdegradation of HER2 was calculated as follows:% HER2 degraded=[(MFI untreated cells−MFI treated cells)/MFI untreatedcell]×100

The HER2 degradation ability of selected compounds of the inventionbased on this assay is summarized in Table 2. IC₅₀ is defined as theconcentration at which there was 50% degradation of the HER2/Neuprotein.

Example D MTS Assay

MTS assays measures the cytotoxicity of geldanamycin derivatives. MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoliumis a tetrazolium dye that is converted to a formazan product bydehydrogenase enzymes of metabolically active cells (Corey, A. et al.“Use of an aqueous soluble tetrazolium/formazan assay for cell growthassays in culture,” Cancer Commun. 1991, 3, 207-212). Cells were seededin 96 well plates at 2000 cells/well and allowed to adhere overnight inDulbecco's modified Eagle's medium supplemented with 10% fetal bovineserum. The final culture volume was 100 μl. Viable cell number wasdetermined by using the Celltiter 96 AQ_(ueous) Non-radioactive CellProliferation Assay (Promega, Madison Wis.). The MTS /PMS (phenazinemethosulfate) solution was mixed at a ratio of 20:1, and 20 μL was addedper well to 100 μl of culture medium. After 2-4 hours, the formation ofthe formazan product was measured at 490 nm absorbance using a multiwellplate spectrophotometer. Background was determined by measuring the Abs490 nm of cell culture medium and MTS-PMS in the absence of cells andwas subtracted from all values. Percent viable cells was calculated asfollows:% viable cells=(Abs at 490 nm treated cells/Abs at 490 nm untreatedcells)×100

The effect of selected compounds of the invention on MCF7 breastcarcinoma cells according to the MTS assay is summarized in Table 2.IC₅₀ was defined as the concentration of the compound which gave rise to50% viable cell number. TABLE 2 Biological Activities of SelectedCompounds of the Invention Lysate MTS binding HER2 IC₅₀ S.No Ex #Structure (μM) IC₅₀ (μM) (μM) 1 7

0.14 0.05  0.13 2 8

ND 0.14 0.5 3 9

ND 0.09 0.3 4 31

ND 0.05 0.3 5 32

ND 0.04  0.08 6 33

ND 0.16 0.6 7 34

ND 0.12 1.0 8 30

ND 0.11 1.0 9 29

0.1  0.85 1.0 10 35

0.08 0.02 1.0 11 10

0.06 0.03 0.7 12 23

ND 0.04 0.1 13 14

0.11 0.09 1.0 14 26

0.09 0.05 ND 15 15

ND 0.9 ND 16 25

ND 0.03 0.3 17 28

ND 0.04 1.0 18 24

ND 0.03 1.0ND = not determined

The foregoing examples are not limiting and are merely illustrative ofvarious aspects and embodiments of the present invention. All documentscited herein are indicative of the levels of skill in the art to whichthe invention pertains and are incorporated by reference herein in theirentireties. None, however, is admitted to be prior art.

One skilled in the art will readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described illustrate preferred embodiments, areexemplary, and are not intended as limitations on the scope of theinvention. Certain modifications and other uses will occur to thoseskilled in the art, and are encompassed within the spirit of theinvention, as defined by the scope of the claims.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. The terms and expressionswhich have been employed are used as terms of description and not oflimitation, and there is no intention in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed, or portions thereof. It is recognized that variousmodifications are possible within the scope of the invention claimed.Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments, optional features,modifications and variations of the concepts herein disclosed may beresorted to by those skilled in the art, and that such modifications andvariations are considered to be within the scope of this invention asdefined by the description and the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, e.g.,genuses, those skilled in the art will recognize that the invention isalso thereby described in terms of any individual member or subgroup ofmembers of the Markush group or subgenus, and exclusions of individualmembers as appropriate, e.g., by proviso.

Other embodiments are within the following claims.

1. A compound represented by Formula I, or a polymorph, solvate, ester,tautomer, enantiomer, pharmaceutically acceptable salt or prodrugthereof:

wherein: R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl; R² is —NHR⁸; R³ isselected from the group consisting of hydrogen, halogen, —SR⁸, —OR⁸,—CN, —C(O)R⁹, —CO₂H, —NO₂, —NR⁸R¹⁰, lower alkyl, lower alkenyl, loweralkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic andheterocyclic, all optionally substituted, wherein: the aryl, heteroaryl,alicyclic and heterocyclic groups are optionally mono-, bi- ortri-cyclic, R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ringatoms and optionally 1-2 of the ring atoms are heteroatoms selected fromthe group of O, S and N, and the optional substituents on R³ areselected from the group consisting of halogen, lower alkyl, loweralkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)R⁹, —C(O)OH, —NO₂, —NR⁸R¹⁰lower aryl, lower heteroaryl, lower alicyclic, lower heterocyclic,arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino,diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl,guanidine, pyridinyl, thiophene, furanyl, indole, indazole,phosphonates, phosphates, phosphoramides, sulfonates, sulfones,sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides,wherein R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ringatoms and optionally 1-3 of the ring atoms are heteroatoms selected fromthe group of O, S and N; R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein the arylgroup is substituted with 3 to 5 substituents, the heteroaryl group issubstituted with 2 to 5 substituents, the alicyclic group is substitutedwith 3 to 5 substituents, the heterocyclic group is substituted with 3to 5 substituents, and the substituents on R⁵ are selected from thegroup consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,—SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹ wherein R¹¹ and R¹¹ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lowerheteroaryl; R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower arylor lower heteroaryl; and R¹² is hydrogen or lower alkyl.
 2. The compoundof claim 1 or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, wherein: R¹ ishalogen or lower alkyl; R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹;and R⁵ is aryl or heteroaryl, wherein each of said aryl and heteroarylgroups is monocyclic or bicyclic.
 3. The compound of claim 1, or apolymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein: R² is —NH₂; R³ is selectedfrom hydrogen, halogen, —SR⁸, —OR⁸, —CN, —NR⁸R¹⁰, lower alkyl, loweralkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, lowerheteroaryl, lower alicyclic, and lower heterocyclic, wherein R⁸ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lowerheteroaryl, and wherein R⁸ and R¹⁰ taken together optionally form a ringof 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; and R⁵ is aryl or heteroaryl,wherein each of said aryl and heteroaryl groups is monocyclic orbicyclic.
 4. The compound of claim 1, or a polymorph, solvate, ester,tautomer, enantiomer, pharmaceutically acceptable salt or prodrugthereof, wherein: R¹ is halogen or lower alkyl; R² is —NH₂; R⁴ is—(CH₂)—; and R⁵ is aryl, heteroaryl, alicyclic or heterocyclic, whereineach of said aryl, heteroaryl alicyclic or heterocyclic groups ismonocyclic or bicyclic.
 5. The compound of claim 1, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, wherein R¹ is halogen; R² is —NH₂; R³ is hydrogen,halogen, —SR⁸, —OR⁸, lower alkyl, lower aryl, lower heteroaryl, or—NR⁸R¹⁰, wherein R⁸ and R¹⁰ taken together optionally form a ring of 3-7ring atoms and optionally 1-3 of the ring atoms are heteroatoms selectedfrom the group of O, S and N; R⁴ is —CH₂—; and R⁵ is aryl or heteroaryl,wherein each of said aryl and heteroaryl groups is monocyclic orbicyclic.
 6. The compound of claim 5, or a polymorph, solvate, ester,tautomer, enantiomer, pharmaceutically acceptable salt or prodrugthereof, wherein R¹ is chloro or bromo; and R⁵ is a phenyl having 3 to 5substituents.
 7. The compound of claim 5, or a polymorph, solvate,ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrugthereof, wherein R¹ is chloro or bromo; and R⁵ is a pyridyl having 3 to5 substituents.
 8. The compound of claim 5, or a polymorph, solvate,ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrugthereof, wherein R¹ is chloro or bromo; and R⁵ is an 1 -oxy-pyridyl(N-oxy-pyridyl) having 3 to 5 substituents.
 9. The compound of claim 5,wherein said compound is a member selected from the group below, or apolymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof:


10. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


11. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


12. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


13. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


14. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


15. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


16. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


17. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


18. The compound of claim 5, wherein said compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


19. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


20. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


21. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


22. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


23. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


24. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


25. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


26. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


27. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


28. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


29. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


30. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


31. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


32. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


33. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


34. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


35. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


36. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


37. The compound of claim 5, wherein said compound is represented by theformula below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:


38. A pharmaceutical composition comprising one or more pharmaceuticalacceptable excipients and at least one compound represented by Formula Ibelow, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:

wherein: R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl; R² is —NHR⁸; R³ isselected from the group consisting of hydrogen, halogen, —SR⁸, —OR⁸,—CN, —C(O)R⁹, —CO₂H, —NO₂, —NR⁸R¹⁰, lower alkyl, lower alkenyl, loweralkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic andheterocyclic, all optionally substituted, wherein: the aryl, heteroaryl,alicyclic and heterocyclic groups are optionally mono-, bi- ortri-cyclic, R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ringatoms and optionally 1-2 of the ring atoms are heteroatoms selected fromthe group of O, S and N, and the optional substituents on R³ areselected from the group consisting of halogen, lower alkyl, loweralkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)R⁹, —C(O)OH, —NO₂,—NR⁸R¹⁰, lower aryl, lower heteroaryl, lower alicyclic, lowerheterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino,dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy,perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole,phosphonates, phosphates, phosphoramides, sulfonates, sulfones,sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides,wherein R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ringatoms and optionally 1-3 of the ring atoms are heteroatoms selected fromthe group of O, S and N; R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein the arylgroup is substituted with 3 to 5 substituents, the heteroaryl group issubstituted with 2 to 5 substituents, the alicyclic group is substitutedwith 3 to 5 substituents, the heterocyclic group is substituted with 3to 5 substituents, and the substituents on R⁵ are selected from thegroup consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,—SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lowerheteroaryl; R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower arylor lower heteroaryl; and R¹² is hydrogen or lower alkyl.
 39. Thepharmaceutical composition of claim 38, wherein: R¹ is halogen or loweralkyl; R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹; and R⁵ is aryl orheteroaryl, wherein each of said aryl and heteroaryl groups ismonocyclic or bicyclic.
 40. The pharmaceutical composition of claim 38,wherein: R¹ is halogen; R² is —NH₂; R³ is hydrogen, halogen, —SR⁸, —OR⁸,lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, loweraryl, lower heteroaryl, or —NR⁸R¹⁰, wherein R⁸ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R⁴ is—CH₂—; and R⁵ is aryl or heteroaryl, wherein each of said aryl andheteroaryl groups is monocyclic or bicyclic.
 41. The pharmaceuticalcomposition of claim 40, wherein R¹ is chloro or bromo; and R⁵ is aphenyl having 3 to 5 substituents.
 42. The pharmaceutical composition ofclaim 40, wherein R¹ is chloro or bromo; and R⁵ is a pyridyl having 3 to5 substituents.
 43. The pharmaceutical composition of claim 40, whereinR¹ is chloro or bromo; and R⁵ is a 1-oxy-pyridyl (N-oxy-pyridyl) having3 to 5 substituents.
 44. A method of treating an individual having anHSP90 mediated disorder comprising administering to said individual apharmaceutical composition comprising a pharmaceutically effectiveamount of a compound of Formula I:

or a polymorph, solvate, ester, tautomer, pharmaceutically acceptablesalt or prodrug thereof, wherein: R¹ is halogen, —OR¹¹ —SR¹¹ or loweralkyl; R² is —NHR⁸; R³ is selected from the group consisting ofhydrogen, halogen, —SR⁸, —OR⁸, —CN, —C(O)R⁹, —CO₂H, —NO₂, —NR⁸R¹⁰, loweralkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl,heteroaryl, alicyclic and heterocyclic, all optionally substituted,wherein: the aryl, heteroaryl, alicyclic and heterocyclic groups areoptionally mono-, bi- or tri-cyclic; R⁸ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-2 of the ringatoms are heteroatoms selected from the group of O, S and N, and theoptional substituents on R³ are selected from the group consisting ofhalogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN,—C(O)R⁹, —C(O)OH, —NO₂, —NR⁸R¹⁰, lower aryl, lower heteroaryl, loweralicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁴ is —CHR¹²—, —C(O), —C(S),—S(O)—, or —SO₂—; R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic,wherein the aryl group is substituted with 3 to 5 substituents, theheteroaryl group is substituted with 2 to 5 substituents, the alicyclicgroup is substituted with 3 to 5 substituents, the heterocyclic group issubstituted with 3 to 5 substituents, and the substituents on R⁵ areselected from the group consisting of halogen, lower alkyl, loweralkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂ and—NR⁸R¹⁰ lower aryl, heteroaryl, alicyclic, lower heterocyclic,arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino,diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl,guanidine, pyridinyl, thiophene, furanyl, indole, indazole,phosphonates, phosphates, phosphoramides, sulfonates, sulfones,sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides,wherein R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ringatoms and optionally 1-3 of the ring atoms are heteroatoms selected fromthe group of O, S and N; R⁸ is hydrogen, lower alkyl, lower alkenyl,lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹; R⁹ is hydrogen,lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl,—NR¹⁰ R¹⁰ or —OR”, wherein R¹⁰ and R¹⁰ taken together optionally form aring of 3-7 ring atoms and optionally 1-3 of the ring atoms areheteroatoms selected from the group of O, S and N; R¹⁰ is hydrogen,lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lowerheteroaryl; R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower arylor lower heteroaryl; and R¹² is hydrogen or lower alkyl.
 45. The methodof claim 44, wherein: R¹ is halogen or lower alkyl; R²is —NHR⁸, where R⁸is hydrogen or —C(O)R⁹; and R⁵ is aryl or heteroaryl, wherein each ofsaid aryl and heteroaryl groups is monocyclic or bicyclic.
 46. Themethod of claim 44, wherein: R² is —NH₂; R³ is selected from hydrogen,halogen, —SR⁸, —OR⁸, —CN, —NR⁸R¹⁰, lower alkyl, lower alkenyl, loweralkynyl, lower perhaloalkyl, lower aryl, lower heteroaryl, loweralicyclic, and lower heterocyclic, wherein R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl, andwherein R⁸ and R¹⁰ taken together optionally form a ring of 3-7 ringatoms and optionally 1-3 of the ring atoms are heteroatoms selected fromthe group of O, S and N; and R⁵ is aryl or heteroaryl, wherein each ofsaid aryl and heteroaryl groups is monocyclic or bicyclic.
 47. Themethod of claim 44, wherein: R¹ is halogen or lower alkyl; R² is —NH₂;R⁴ is —(CH₂)—; and R⁵ is aryl, heteroaryl, alicyclic or heterocyclic,wherein each of said aryl, heteroaryl alicyclic or heterocyclic groupsis monocyclic or bicyclic.
 48. The method of claim 44, wherein: R¹ ishalogen; R² is —NH₂; R³ is hydrogen, halogen, —SR⁸, —OR⁸, lower alkyl,lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, lowerheteroaryl, or —NR⁸R¹⁰ wherein R⁸ and R¹⁰ when taken together optionallyform a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms areheteroatoms selected from the group of O, S and N; R⁴ is —CH₂—; and R⁵is aryl or heteroaryl, wherein each of said aryl and heteroaryl groupsis monocyclic or bicyclic.
 49. The method of claim 48, wherein R¹ ischloro or bromo; and R⁵ is a phenyl having 3 to 5 substituents.
 50. Themethod of claim 48, wherein R¹ is chloro or bromo; and R⁵ is a pyridylhaving 3 to 5 substituents.
 51. The method of claim 48, wherein R¹ ischloro or bromo; and R⁵ is a 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5substituents.
 52. The method of claim 44, wherein the HSP90-mediateddisorder is selected from the group of inflammatory diseases,infections, autoimmune disorders, stroke, ischemia, cardiac disorders,neurological disorders, fibrogenetic disorders, proliferative disorders,tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases,and malignant disease.
 53. The method of claim 52 wherein thefibrogenetic disorder is further selected from the group of scleroderma,polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis,keloid formation, interstitial nephritis and pulmonary fibrosis.
 54. Themethod of claim 44 further comprising administering at least onetherapeutic agent selected from the group of cytotoxic agents,anti-angiogenesis agents and anti-neoplastic agents.
 55. The method ofclaim 54 wherein the at least one anti-neoplastic agent is selected fromthe group of alkylating agents, anti-metabolites, epidophyllotoxins;antineoplastic enzymes, topoisomerase inhibitors, procarbazines,mitoxantrones, platinum coordination complexes, biological responsemodifiers and growth inhibitors, hormonal/anti-hormonal therapeuticagents, and haematopoietic growth factors.
 56. A compound represented byFormula II, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:

wherein: R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl; R² is —NHR⁸; R⁴ is—CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—; R⁵ is aryl, heteroaryl,alicyclic, or heterocyclic, wherein the aryl group is substituted with 3to 5 substituents, the heteroaryl group is substituted with 2 to 5substituents, the alicyclic group is substituted with 3 to 5substituents, the heterocyclic group is substituted with 3 to 5substituents, and the substituents on R⁵ are selected from the groupconsisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸,—OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lowerheteroaryl; R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower arylor lower heteroaryl; R¹² is hydrogen or lower alkyl; and R¹⁵ ishydrogen, lower alkyl, lower alkenyl or lower alkynyl.
 57. The compoundof claim 56, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof: R² is —NHR⁸, whereR⁸ is hydrogen or —C(O)R⁹; R⁵ is aryl, heteroaryl, alicyclic, orheterocyclic, all optionally mono-, bi- or tri-cyclic; and R⁹ is loweralkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl. 58.The compound of claim 56, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof: R¹ ishalogen or lower alkyl; R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹; R⁴is —(CH₂)—; and R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, alloptionally mono-, bi- or tri-cyclic.
 59. The compound of claim 58, or apolymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein R¹ is chloro or bromo; R² is—NH₂; and R⁵ is a phenyl having 3 to 5 substituents.
 60. The compound ofclaim 58, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, wherein R¹ ischloro or bromo; R² is —NH₂, and R⁵ is a pyridyl having 3 to 5substituents.
 61. The compound of claim 58, or a polymorph, solvate,ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrugthereof, wherein R¹ is chloro or bromo; R² is —NH₂, and R⁵ is an1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.
 62. Apharmaceutical composition comprising one or more pharmaceuticalacceptable excipients and at least one compound represented by FormulaII below, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof:

wherein R¹ is halogen, —OR¹¹, —SR” or lower alkyl; R² is —NHR⁸; R⁴ is—CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—; R⁵ is aryl, heteroaryl,alicyclic, or heterocyclic, wherein the aryl group is substituted with 3to 5 substituents, the heteroaryl group is substituted with 2 to 5substituents, the alicyclic group is substituted with 3 to 5substituents, the heterocyclic group is substituted with 3 to 5substituents, and the substituents on R⁵ are selected from the groupconsisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸,—OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂ and —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,lower heteroaryl, —NR¹⁰R¹⁰ or —OR”, wherein R¹⁰ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lowerheteroaryl; R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower arylor lower heteroaryl; R¹² is hydrogen or lower alkyl; and R¹⁵ ishydrogen, lower alkyl, lower alkenyl or lower alkynyl.
 63. Apharmaceutical composition of claim 62, wherein: R¹ is halogen or loweralkyl; R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹; R⁴ is —(CH₂)—; andR⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, all optionallymono-, bi- or tri-cyclic.
 64. A method of treating an individual havingan HSP90 mediated disorder comprising administering to said individual apharmaceutical composition comprising a pharmaceutically effectiveamount of a compound of Formula II:

or a polymorph, solvate, ester, tautomer, pharmaceutically acceptablesalt or prodrug thereof, wherein: R¹ is halogen, —OR¹¹, —SR¹¹ or loweralkyl; R² is —NHR⁸; R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—; R⁵ isaryl, heteroaryl, alicyclic, or heterocyclic, wherein the aryl group issubstituted with 3 to 5 substituents, the heteroaryl group issubstituted with 2 to 5 substituents, the alicyclic group is substitutedwith 3 to 5 substituents, the heterocyclic group is substituted with 3to 5 substituents, and the substituents on R⁵ are selected from thegroup consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,—SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,lower heteroaryl, —NR¹⁰R¹⁰ or —OR”, wherein R¹⁰ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lowerheteroaryl; R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower arylor lower heteroaryl; R¹² is hydrogen or lower alkyl; and R¹⁵ ishydrogen, lower alkyl, lower alkenyl or lower alkynyl.
 65. The method ofclaim 64, wherein: R¹ is halogen or lower alkyl; R² is —NHR⁸, where R ishydrogen or —C(O)R⁹; R⁴ is —(CH₂)—; and R⁵ is aryl, heteroaryl,alicyclic, or heterocyclic, all optionally mono-, bi- or tri-cyclic. 66.A compound, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, prepared by the process comprising:reacting a compound of Formula Y and a compound of Formula Z, wherein: Yis represented by the following formulae:

Z is L¹-R⁴-R⁵; wherein: L¹ is halogen, NR⁸R¹⁰ triflate, tosylate, ormesylate; R⁴ is —(CHR¹²)—, —C(O), —C(S), —S(O)—, or —SO₂—; R⁵ is aryl,heteroaryl, alicyclic, or heterocyclic, wherein the aryl group issubstituted with 3 to 5 substituents, the heteroaryl group issubstituted with 2 to 5 substituents, the alicyclic group is substitutedwith 3 to 5 substituents, the heterocyclic group is substituted with 3to 5 substituents, and the substituents on R⁵ are selected from thegroup consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,—SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lowerheteroaryl; R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower arylor lower heteroaryl; R¹² is hydrogen or lower alkyl; R²¹ is halogen,—OR⁸, —SR⁸ or lower alkyl; R²² is —NR⁸R¹⁰; R²³ is hydrogen, —OH or itsketo tautomer, —OR⁸, halogen, —CN, lower alkyl, lower aryl or —C(O)R⁹;R²⁴ is —CHO, —NH₂, —NO₂ or —NO; R²⁵ is halogen or —OH; R²⁶ is —C(O)NH₂or C(O)OEt; and R²⁷ is —NH₂, —OH or halogen.
 67. The compound of claim66, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein R⁵ is aryl, heteroaryl,alicyclic, or heterocyclic, optionally mono- or bicyclic.
 68. Thecompound of claim 67, or a polymorph, solvate, ester, tautomer,pharmaceutically acceptable salt or prodrug thereof, wherein L¹ is —Cl,—Br or —NH₂; R⁴ is —CH₂—; R⁵ is aryl or heteroaryl.
 69. The compound ofclaim 67, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein Y is a pyrazolopyrimidine.70. The compound of claim 67, or a polymorph, solvate, ester, tautomer,pharmaceutically acceptable salt or prodrug thereof, wherein saidreaction is performed in a solvent comprising a member selected from thegroup of DMF, THF and DMSO.
 71. The compound of claim 67, or apolymorph, solvate, ester, tautomer, pharmaceutically acceptable salt orprodrug thereof, wherein said reaction is performed in a solvent thatcomprises DMF.